Hot topics in pharmacology

Recent publications of interest recommended by NC-IUPHAR

2018: Jan | Feb | Mar | Apr | May | Jun | Jul | Aug | Sep | Oct | Nov

November 2018

Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function
(1) Shifrut E et al. (2018). Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function. Cell, pii: S0092-8674(18)31333-3. doi: 10.1016/j.cell.2018.10.024. [PMID:]


Doing it All - How Families are Reshaping Rare Disease Research
(1) Ekins S & Peristein EO (2018). Doing it All - How Families are Reshaping Rare Disease Research. Pharm Res, 35(10):192. doi: 10.1007/s11095-018-2481-7. [PMID:]


Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states
(1) Manolaridis et al. (2018). Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states. Nature, 563(7731):426-430. doi: 10.1038/s41586-018-0680-3. [PMID:]


Conformational ensemble of the human TRPV3 ion channel
(1) Zubcevic L et al. (2018). Conformational ensemble of the human TRPV3 ion channel. Nat Commun, 9(1):4773. doi: 10.1038/s41467-018-07117-w. [PMID:]


Binding Kinetics Survey of the Drugged Kinome
(1) Georgi V et al. (2018). Binding Kinetics Survey of the Drugged Kinome. J Am Chem Soc, 140(46):15774-15782. doi: 10.1021/jacs.8b08048. [PMID:]


Somatic APP gene recombination in Alzheimer’s disease and normal neurons
(1) Lee MH et al. (2018). Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature, doi: 10.1038/s41586-018-0718-6. [Epub ahead of print]. [PMID:]


Quantitative Interpretation of Intracellular Drug Binding and Kinetics Using the Cellular Thermal Shift Assay
(1) Seashore-Ludlow B et al. (2018). Quantitative Interpretation of Intracellular Drug Binding and Kinetics Using the Cellular Thermal Shift Assay. Biochemistry, doi: 10.1021/acs.biochem.8b01057. [Epub ahead of print]. [PMID:]


Assembly of a pan-genome from deep sequencing of 910 humans of African descent
(1) Sherman RM et al. (2018). Assembly of a pan-genome from deep sequencing of 910 humans of African descent. Nat Genet, doi: 10.1038/s41588-018-0273-y. [Epub ahead of print]. [PMID:]


Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation
(1) Visnes T (2018). Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. Science, 362(6416):834-839. doi: 10.1126/science.aar8048. [PMID:]


Be open about drug failures to speed up research
(1) Alteri E & Guizzaro L (2018). Be open about drug failures to speed up research. Nature, 563(7731):317-319. doi: 10.1038/d41586-018-07352-7. [PMID:]


Seven Year Itch: Pan-Assay Interference Compounds (PAINS) in 2017-Utility and Limitations (Jan 2018)
(1) Baell JB & Nissick JWM (2018). Seven Year Itch: Pan-Assay Interference Compounds (PAINS) in 2017-Utility and Limitations. ACS Chem Biol, 13(1):36-44. doi: 10.1021/acschembio.7b00903. [PMID:]


Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders
(1) Ligthart S et al. (2018). Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. Am J Hum genet, 103(5):691-706. doi: 10.1016/j.ajhg.2018.09.009. [PMID:]


Nanopore native RNA sequencing of a human poly(A) transcriptome
(1) Workman RE et al. (2018). Nanopore native RNA sequencing of a human poly(A) transcriptome. bioRxiv, doi: https://doi.org/10.1101/460410. [bioRxiv:]


Increased Obesity Is Causal for Increased Inflammation—A Mendelian Randomisation Study
(1) van Zuydam N et al. (2018). Increased Obesity Is Causal for Increased Inflammation—A Mendelian Randomisation Study. Diabetes, late breaking poster session, 67(supp 1), doi: https://doi.org/10.2337/db18-217-LB. [Diabetes:]


Crystal structure of human endothelin ETB receptor in complex with peptide inverse agonist IRL2500
(1) Nagiri C et al. (2018). Crystal structure of human endothelin ETB receptor in complex with peptide inverse agonist IRL2500. bioRxiv, doi: https://doi.org/10.1101/460410. [bioRxiv:]


The metabolite BH4 controls T cell proliferation in autoimmunity and cancer
(1) Cronin SJF et al. (2018). The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature, 563(7732):564-568. doi: 10.1038/s41586-018-0701-2. [PMID:]


The signalling conformation of the insulin receptor ectodomain
(1) Weis F et al. (2018). The signalling conformation of the insulin receptor ectodomain. Nat Commun, 144:244-255. 9(1):4420. doi: 10.1038/s41467-018-06826-6. [PMID:]


Drug-receptor kinetics and sigma-1 receptor affinity differentiate clinically evaluated histamine H3 receptor antagonists
(1) Riddy DM et al. (2018). Drug-receptor kinetics and sigma-1 receptor affinity differentiate clinically evaluated histamine H3 receptor antagonists. Neuropharmacology, 144:244-255. doi: 10.1016/j.neuropharm.2018.10.028. [Epub ahead of print]. [PMID:]


Joining Forces: The Chemical Biology-Medicinal Chemistry Continuum (Sept 2017)
(1) Plowright AT et al. (2018). Joining Forces: The Chemical Biology-Medicinal Chemistry Continuum. Chem Cell Biol, 24(9):1058-1065. doi: 10.1016/j.chembiol.2017.05.019. [PMID:]


MoonDB 2.0: an updated database of extreme multifunctional and moonlighting proteins
(1) Ribeiro DM et al. (2018). MoonDB 2.0: an updated database of extreme multifunctional and moonlighting proteins. Nucleic Acids Res, doi: 10.1093/nar/gky1039. [Epub ahead of print]. [PMID:]


October 2018

The Future of Computational Chemogenomics
(1) Jacoby E & Brown JB (2018). The Future of Computational Chemogenomics. Computational Chemogenomics, pp 425-450. [SpringerLink:]


Slc7a5 regulates Kv1.2 channels and modifies functional outcomes of epilepsy-linked channel mutations
(1) Baronas VA et al. (2018). Slc7a5 regulates Kv1.2 channels and modifies functional outcomes of epilepsy-linked channel mutations. Nat Commun, 9(1):4417. doi: 10.1038/s41467-018-06859-x. [PMID:]




Comments by Alistair Mathie () and Emma L. Veale (), The Medway School of Pharmacy

Piezo channels (Piezo1 and Piezo2) are excitatory ion channels which respond directly to a variety of forms of mechanical stimuli. Two recent papers describe some of the critical roles of Piezo channels in sensory neuron transduction (1, 2). In the first, Murthy et al. (1) demonstrate that Piezo2 mediates both inflammatory and nerve-injury sensitized mechanical pain in mice. In the second, Zeng et al. (2), show that both Piezo1 and Piezo2 are responsible for the baro-receptor reflex that regulates blood pressure and cardiac function.

(1) Murthy SE et al. (2018). The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice. Sci Transl Med, 10(462). pii: eaat9897. doi: 10.1126/scitranslmed.aat9897. [PMID: ].

(2) Zeng WZ et al. (2018). PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science, 362(6413):464-467. doi: 10.1126/science.aau6324. [PMID: ].


A comprehensive analysis of the usability and archival stability of omics computational tools and resources
(1) Mangul S et al. (2018). A comprehensive analysis of the usability and archival stability of omics computational tools and resources. bioRxiv, doi: https://doi.org/10.1101/452532. [bioRxiv:]


Gene expression variability across cells and species shapes innate immunity
(1) Hagai T et al. (2018). Gene expression variability across cells and species shapes innate immunity. Nature, doi: 10.1038/s41586-018-0657-2. [Epub ahead of print]. [PMID:]


From the Human Cell Atlas to dynamic immune maps in human disease
(1) Adlung L & Amit I. (2018). From the Human Cell Atlas to dynamic immune maps in human disease. Nat Rev Immunol, 18(10):597-598. doi: 10.1038/s41577-018-0050-2. [PMID:]


Two Decades under the Influence of the Rule of Five and the Changing Properties of Approved Oral Drugs
(1) Schultz MD. (2018). Two Decades under the Influence of the Rule of Five and the Changing Properties of Approved Oral Drugs. J Med Chem, doi: 10.1021/acs.jmedchem.8b00686. [Epub ahead of print]. [PMID:]




Comments by Steve Alexander, IUPHAR/BPS Meebo-online.info, ()

This report [1] from the National Institute on Drug Abuse in the USA focusses on the role of RTP type D on reward associated with cocaine administration. They identify that RTP type D heterozygous knockout mice exhibit lower reward responses to cocaine, and that a novel small molecule that appears to target the enzymatic function of RTP type D is able to reduce cocaine-induced place preference and self-administration in wild type, but not heterozygous knockout mice.

(1) Uhl GR et al. (2018). Cocaine reward is reduced by decreased expression of receptor-type protein tyrosine phosphatase D (PTPRD) and by a novel PTPRD antagonist. Proc Natl Acad Sci USA, pii: 201720446. doi: 10.1073/pnas.1720446115. [Epub ahead of print]. [PMID: ]


Genenames.org: the HGNC and VGNC resources in 2019
(1) Braschi B et al. (2018). Genenames.org: the HGNC and VGNC resources in 2019. Nucleic Acids Res, 5:180230. doi: 10.1093/nar/gky930. [Epub ahead of print]. [PMID:]


A large-scale dataset of in vivo pharmacology assay results
(1) Swaminathan J et al. (2018). A large-scale dataset of in vivo pharmacology assay results. Nat Biotechnol, 5:180230. doi: 10.1038/nbt.4278. [Epub ahead of print]. [PMID:]


A large-scale dataset of in vivo pharmacology assay results
(1) Hunter FMI et al. (2018). A large-scale dataset of in vivo pharmacology assay results. Sci Data, 5:180230. doi: 10.1038/sdata.2018.230. [PMID:]


Structure of the human voltage-gated sodium channel Nav1.4 in complex with β1
(1) Pan X et al. (2018). Structure of the human voltage-gated sodium channel Nav1.4 in complex with β1. Science, 362(6412). pii: eaau2486. doi: 10.1126/science.aau2486. [PMID:]


Rapid structure determination of microcrystalline molecular compounds using electron diffraction
(1) Gruene T et al. (2018). Rapid structure determination of microcrystalline molecular compounds using electron diffraction. Angew Chem Int Ed Eng, doi: 10.1002/anie.201811318. [Epub ahead of print]. [PMID:]


Impact of Human Genetics on Drug R&D
(1) Plenge R (2018). Impact of Human Genetics on Drug R&D - Slideset. ASHG, doi: 10.1002/anie.201811318. [Epub ahead of print]. []


DRUG-seq for miniaturized high-throughput transcriptome profiling in drug discovery
(1) Ye C et al. (2018). DRUG-seq for miniaturized high-throughput transcriptome profiling in drug discovery. Nat Commun, 9(1):4307. doi: 10.1038/s41467-018-06500-x. [PMID:]


Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration
(1) Ryu JK et al. (2018). Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat Immunol, 19(11):1212-1223. doi: 10.1038/s41590-018-0232-x. [PMID:]


Drug repurposing: progress, challenges and recommendations
(1) Pushpakom S et al. (2018). Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov, doi: 10.1038/nrd.2018.168. [Epub ahead of print]. [PMID:]


Regulatory T cells in the treatment of disease
(1) Sharabi A et al. (2018). Regulatory T cells in the treatment of disease. Nat Rev Drug Discov, 562(7726):181-183. doi: 10.1038/d41586-018-06956-3. [PMID:]


The approach to predictive medicine that is taking genomics research by storm
(1) Warren M (2018). The approach to predictive medicine that is taking genomics research by storm. Nature, 562(7726):181-183. doi: 10.1038/d41586-018-06956-3. [PMID:]


The UK Biobank resource with deep phenotyping and genomic data
(1) Bycroft C et al. (2018). The UK Biobank resource with deep phenotyping and genomic data. Nature, 62(7726):203-209. doi: 10.1038/s41586-018-0579-z. [PMID:]


How Selective Are Pharmacological Inhibitors of Cell-Cycle-Regulating Cyclin-Dependent Kinases?
(1) Jorda R et al. (2018). How Selective Are Pharmacological Inhibitors of Cell-Cycle-Regulating Cyclin-Dependent Kinases? J Med Chem, 61(20):9105-9120. doi: 10.1021/acs.jmedchem.8b00049. [PMID:]


Advanced model systems and tools for basic and translational human immunology
(1) Wager LE, DiFazio RM & Davis MM (2018). Advanced model systems and tools for basic and translational human immunology. Genome Med, 10(1):73. doi: 10.1186/s13073-018-0584-8. [PMID:]


Where Do Recent Small Molecule Clinical Development Candidates Come From?
(1) Brown DG & Boström J (2018). Where Do Recent Small Molecule Clinical Development Candidates Come From? J Med Chem, doi: 10.1021/acs.jmedchem.8b00675. [Epub ahead of print]. [PMID:]


Orally Active Peptides: Is There a Magic Bullet?
(1) Räder AFB et al. (2018). Orally Active Peptides: Is There a Magic Bullet? Agnew Chem Int Ed Eng, 57(44):14414-14438. doi: 10.1002/anie.201807298. [PMID:]


LipidPedia: a comprehensive lipid knowledgebase
(1) Kuo TC & Tseng YJ (2018). LipidPedia: a comprehensive lipid knowledgebase. Bioinformatics, doi: 10.1093/bioinformatics/bty213. [Epub ahead of print]. [PMID:]


Launching the C-HPP pilot project for functional characterization of identified proteins with no known function
(1) Paik YK et al. (2018). Launching the C-HPP pilot project for functional characterization of identified proteins with no known function. J Proteome Res, doi: 10.1021/acs.jproteome.8b00383. [Epub ahead of print]. [PMID:]


International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans
(1) Sieghart W & Savić MM (2018). International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans. Pharmacol Rev, 70(4):836-878. doi: 10.1124/pr.117.014449. [PMID:]


Uncovering new disease indications for G-protein coupled receptors and their endogenous ligands
(1) Freudenberg JM et al. (2018). Uncovering new disease indications for G-protein coupled receptors and their endogenous ligands. BMC Bioinformatics, 19(1):345. doi: 10.1186/s12859-018-2392-y. [PMID:]


Structural basis for σ1 receptor ligand recognition
(1) Schmidt HR et al. (2018). Structural basis for σ1 receptor ligand recognition. Nat Struct Mol Biol, 25(10):981-987. doi: 10.1038/s41594-018-0137-2. [PMID:]


The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis
(1) Janes J et al. (2018). The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis. Proc Natl Acad Sci USA, 115(42):10750-10755. doi: 10.1073/pnas.1810137115. [PMID:]


September 2018

Accurate classification of BRCA1 variants with saturation genome editing
(1) Findlay GM et al. (2018). Accurate classification of BRCA1 variants with saturation genome editing. Nature, 562(7726):217-222. doi: 10.1038/s41586-018-0461-z. [PMID:]


Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition
(1) Wang L et al. (2018). Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition. Mol Cell, pii: S1097-2765(18)30643-9. doi: 10.1016/j.molcel.2018.08.009. [Epub ahead of print]. [PMID:]


Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits
(1) Evangelou E et al. (2018). Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat Genet, doi: 10.1038/s41588-018-0205-x. [Epub ahead of print]. [PMID:]


Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase
(1) Kiss LE et al. (2018). Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase. Chem Med Chem, doi: 10.1002/cmdc.201800393. [Epub ahead of print]. [PMID:]




Comments by Steve Alexander, IUPHAR/BPS Meebo-online.info, ()

In this multi-author, multi-centre publication [1] lead by Denise Wootten and Patrick Sexton from the Monash Institute of Pharmacological Sciences, there is reported a 3.3 Angstrom structure of one of the more unusual G protein-coupled receptors. The CGRP receptor is a target for the recently FDA-approved monoclonal antibody erenumab targetting migraine. The receptor is unusual because of its modulation by a trio of accessory proteins exemplified here by RAMP1, which influence both the pharmacological and signalling profiles of the GPCR.

(1) Liang YL et al. (2018). Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor. Nature, doi: 10.1038/s41586-018-0535-y. [Epub ahead of print]. [PMID: ]


Large-Scale Reanalysis of Publicly Available HeLa Cell Proteomics Data in the Context of the Human Proteome Project
(1) Robin T et al. (2018). Large-Scale Reanalysis of Publicly Available HeLa Cell Proteomics Data in the Context of the Human Proteome Project. J Proteome Res, doi: 10.1021/acs.jproteome.8b00392. [Epub ahead of print]. [PMID:]


Therapeutic Targeting of Endosomal G-Protein-Coupled Receptors
(1) Thomsen ARB et al. (2018). Therapeutic Targeting of Endosomal G-Protein-Coupled Receptors. Trends Pharmacol Sci, pii: S0165-6147(18)30138-X. doi: 10.1016/j.tips.2018.08.003. [Epub ahead of print]. [PMID:]


Expanding the medicinal chemistry synthetic toolbox
(1) Boström et al. (2018). Expanding the medicinal chemistry synthetic toolbox. Nat Rev Drug Discov, doi: 10.1038/nrd.2018.116. [Epub ahead of print]. [PMID:]


Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts
(1) Wold et al. (2018). Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts. J Med Chem, doi: 10.1021/acs.jmedchem.8b00875. [Epub ahead of print]. [PMID:]


August 2018

Artificial intelligence in drug discovery
(1) Sellwood et al. (2018). Artificial intelligence in drug discovery. J Chem Inf Model, 10(17):2025-2028. doi: 10.4155/fmc-2018-0212. [PMID:]


Characterization of the Chemical Space of Known and Readily Obtainable Natural Products
(1) Chen Y et al. (2018). Characterization of the Chemical Space of Known and Readily Obtainable Natural Products. J Chem Inf Model, 58(8):1518-1532. doi: 10.1021/acs.jcim.8b00302. [PMID:]


Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight
(1) Shi Y & Holtzman DM (2018). Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat Rev Immunol, doi: 10.1038/s41577-018-0051-1. [Epub ahead of print]. [PMID:]




Comments by Jörg Striessnig, University of Innsbruck

This paper [1] extends previous studies demonstrating a key role of voltage-gated L-type Ca2+ channels in the modulation of activity-dependent gene transcription. Earlier work in cultured neurons had already shown that L-type channel activity is required to activate gene expression through different signaling pathways, including the Ras/MAPK pathway (2-4). This is confirmed in the present study (primarily in experiments with HEK-293 cells) but there are important differences in the way nuclear signaling gets activated.

(1) Servili E et al. (2018). β-Subunit of the voltage-gated Ca2+ channel Cav1.2 drives signaling to the nucleus via H-Ras. Proc Natl Acad Sci USA, 115(37):E8624-E8633. doi: 10.1073/pnas.1805380115. [PMID: ]

(2) Dolmetsch RE et al. (2001). Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science, 294(5541):333-9. [PMID: ]

(3) Wu GY et al. (2018). Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Cold Spring Harbor Perspect Biol, 98(5):2808-13. [PMID: ]

(4) Hagenston AM & Bading H (2018). Calcium signaling in synapse-to-nucleus communication. Mol Pharmacol, 3(11):a004564. doi: 10.1101/cshperspect.a004564. [Epub ahead of print]. [PMID: ]


Crystal structure of the Frizzled 4 receptor in a ligand-free state
(1) Yang S et al. (2018). Crystal structure of the Frizzled 4 receptor in a ligand-free state. Nature, 560(7720):666-670. doi: 10.1038/s41586-018-0447-x. [PMID:]


Structural determinants of 5-HT2B receptor activation and biased agonism
(1) McCorvy JD et al. (2018). Structural determinants of 5-HT2B receptor activation and biased agonism. Nat Struct Mol Biol, doi: 10.1038/s41594-018-0116-7. [Epub ahead of print]. [PMID:]


Cryo-EM structures of the human volume-regulated anion channel LRRC8
(1) Kasuya G et al. (2018). Cryo-EM structures of the human volume-regulated anion channel LRRC8. Nat Struct Mol Biol, doi: 10.1038/s41594-018-0109-6. [Epub ahead of print]. [PMID:]


Mechanisms of signalling and biased agonism in G protein-coupled receptors
(1) Wootten D et al. (2018). Mechanisms of signalling and biased agonism in G protein-coupled receptors. Nat Rev Mol Cell Biol, doi: 10.1038/s41580-018-0049-3. [Epub ahead of print]. [PMID:]


Challenges of Connecting Chemistry to Pharmacology: Perspectives from Curating the IUPHAR/BPS Meebo-online.info
(1) Southan C et al. (2018). Challenges of Connecting Chemistry to Pharmacology: Perspectives from Curating the IUPHAR/BPS Meebo-online.info. ACS Omega, 3(7):8408-8420. doi: 10.1021/acsomega.8b00884. [PMID:]


PubChem chemical structure standardization
(1) Hähnke VD et al. (2018). PubChem chemical structure standardization. J Cheminform., 10(1):36. doi: 10.1186/s13321-018-0293-8. [PMID:]


Polypharmacology by Design: A Medicinal Chemist's Perspective on Multitargeting Compounds
(1) Proschak E et al. (2018). Polypharmacology by Design: A Medicinal Chemist's Perspective on Multitargeting Compounds. J Med Chem, doi: 10.1021/acs.jmedchem.8b00760. [Epub ahead of print]. [PMID:]


Co-regulatory networks of human serum proteins link genetics to disease
(1) Emilsson V et al. (2018). Co-regulatory networks of human serum proteins link genetics to disease. Science, pii: eaaq1327. doi: 10.1126/science.aaq1327. [Epub ahead of print]. [PMID:]


July 2018



Comments by Emma L. Veale () and Alistair Mathie ()

The potassium channels KV7.2-KV7.5 (KCNQ2-5; GtoPdb target IDs 561-564) regulate neuronal excitability in the mammalian nervous system. The best characterised neuronal KV7 channels give rise to the M current and are mediated predominantly by hetero-tetramers of KV7.2 and KV7.3 subunits. Established anticonvulsant agents such as retigabine are known to dampen neuronal excitability by activating neuronal KV7 channels. A tryptophan in the S5 transmembrane region of neuronal KV7 channels is essential for retigabine sensitivity with KV7.3 channels particularly sensitive. Importantly, this residue is not present in the cardiac KV7.1 (KCNQ1) channel, reducing the potential for cardiac side effects. Now, a pair of studies (1, 2) has shown that this same region of the channel also contributes to a high affinity binding site for GABA and related metabolites.

(1) Manville RW et al. (2018). Direct neurotransmitter activation of voltage-gated potassium channels. Nat Commun, 9(1):1847. doi: 10.1038/s41467-018-04266-w. [PMID: ]

(2) Manville RW et al. (2018). Gabapentin is a potent activator of KCNQ3 and KCNQ5 potassium channels. Mol Pharmacol, pii: mol.118.112953. doi: 10.1124/mol.118.112953. [Epub ahead of print]. [PMID: ]


All Eyes on Biopharma Trends
(1) Sutton S. (2018). All Eyes on Biopharma Trends. The Medicine Maker, July 2018. [Full text:]


TreeGrafter: phylogenetic tree-based annotation of proteins with Gene Ontology terms and other annotations
(1) Tang H, Finn RD & Thomas PD (2018). TreeGrafter: phylogenetic tree-based annotation of proteins with Gene Ontology terms and other annotations. Bioinformatics, doi: 10.1093/bioinformatics/bty625. [Epub ahead of print]. [PMID:]


VCE-004.3, A Cannabidiol Aminoquinone Derivative, Prevents Bleomycin-induced Skin Fibrosis and Inflammation Through PPARγ AND CB2 -dependent Pathways
(1) Del Rio C et al. (2018). VCE-004.3, A Cannabidiol Aminoquinone Derivative, Prevents Bleomycin-induced Skin Fibrosis and Inflammation Through PPARγ AND CB2 -dependent Pathways. Br J Pharmacology, doi: 10.1111/bph.14450. [Epub ahead of print]. [PMID:]


A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer's disease
(1) Hartl D et al. (2018). A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease. Mol Psychiatry, doi: 10.1038/s41380-018-0091-8. [Epub ahead of print]. [PMID:]


The Assay Guidance Manual: Quantitative Biology and Pharmacology in Preclinical Drug Discovery
(1) Coussens NP et al. (2018). The Assay Guidance Manual: Quantitative Biology and Pharmacology in Preclinical Drug Discovery. Clin Transl Sci, doi: 10.1111/cts.12570. [Epub ahead of print]. [PMID:]


Loose ends: almost one in five human genes still have unresolved coding status
(1) Abascal F et al. (2018). Loose ends: almost one in five human genes still have unresolved coding status. Nucleic Acids Res, doi: 10.1093/nar/gky587. [Epub ahead of print]. [PMID:]


Whole genome sequencing identifies high-impact variants in well-known pharmacogenomic genes
(1) Choi J, Tantisira K & Duan Q (2018). Whole genome sequencing identifies high-impact variants in well-known pharmacogenomic genes. bioRxiv, doi: https://doi.org/10.1101/368225. [bioRxiv:]


Modeling polypharmacy side effects with graph convolutional networks
(1) Zitnik M et al. (2018). Modeling polypharmacy side effects with graph convolutional networks. Bioinformatics, 34(13):i457-i466. doi: 10.1093/bioinformatics/bty294. [PMID:]


Cryo-EM structure of the human neutral amino acid transporter ASCT2
(1) Garaeva AA et al. (2018). Cryo-EM structure of the human neutral amino acid transporter ASCT2. Nat Struct Mol Biol, 25(6):515-521. doi: 10.1038/s41594-018-0076-y. [PMID:]


5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology
(1) Peng Y et al. (2018). 5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. Cell, 172(4):719-730.e14. doi: 10.1016/j.cell.2018.01.001. [PMID:]


Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis
(1) Dennis ASM et al. (2018). Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis. Sci Rep, 8(1):8795. doi: 10.1038/s41598-018-26819-1. [PMID:]


June 2018



Comments by Sadashiva S. Karnik ([email protected]) and Kalyan Tirupula

A new type of deorphanization conundrum confronted in pairing the GPCR, MAS1 with the hormonal peptide angiotensin 1–7 (Ang1-7) was emphasised in recent IUPHAR reviews (1, 2). More evidence for disconnection between Ang1-7 and MAS1 is presented in the recent paper by Gaidarov et al. (3). Ang1-7 is produced by ACE2 or neutral endopeptidase by cleavage of a single amino acid, phenylalanine 8, from angiotensin II (AngII), the major renin angiotensin system hormone. MAS1 was described as the primary receptor for Ang1-7 in regulating diverse biological activities, including vasodilatory, cardio-protective, antithrombotic, antidiuretic and antifibrotic effects (4). These activities are lost in tissues of MAS1-deficient animals, producing striking phenotypes observed in the cardiovascular, renovascular, nervous and reproductive systems. Vast physiological responses to Ang1-7 studied in MAS1-deficient animals serve as the most compelling argument in favor of Ang1-7 pairing with MAS1. However, support for a direct interaction of Ang1-7 with MAS1 lack demonstration of classical G protein signaling and desensitization response to Ang1-7, as well as a lack consensus on confirmatory molecular pharmacological analyses (1, 2).

(1) Gaidarov I et al. (2018). Angiotensin (1–7) does not interact directly with MAS1, but can potently antagonize signaling from the AT1 receptor. Cell Signal, 50:9-24. doi: 10.1016/j.cellsig.2018.06.007. [Epub ahead of print]. [PMID: ]


Biased Ligands of G Protein-Coupled Receptors (GPCRs): Structure-Functional Selectivity Relationships (SFSRs) and Therapeutic Potential
(1) Tan L et al. (2018). Biased Ligands of G Protein-Coupled Receptors (GPCRs): Structure-Functional Selectivity Relationships (SFSRs) and Therapeutic Potential. J Med Chem, doi: 10.1021/acs.jmedchem.8b00435. [Epub ahead of print]. [PMID:]


Structure of a human synaptic GABAA receptor
(1) Zhu S et al. (2018). Structure of a human synaptic GABAA receptor. Nature, 559(7712):67-72. doi: 10.1038/s41586-018-0255-3. [PMID:]




Comments by Steve Alexander, IUPHAR/BPS Meebo-online.info, ()

The A1 adenosine receptor is, for most people, a molecular target they can become conscious of when they block it, which happens frequently. Rapid consumption of higher doses of caffeine, in products like Italian espresso or Turkish coffee, provokes a rapid, transient increase in heart rate and a noticeable increase in limb tremor. In this report, a 3.6 Å structure of the receptor complexed with the endogenous agonist, adenosine, in the presence of the heterotrimeric G12 protein has been resolved by cryo-EM.

(1) Draper-Joyce CJ et al. (2018). Structure of the adenosine-bound human adenosine A1 receptor–Gi complex. Nature, 558, 559-563, doi: 10.1038/s41586-018-0236-6. [Epub ahead of print]. [PMID: ]


Illuminating GPCR Signaling by Cryo-EM
(1) Safdari HA et al. (2018). Illuminating GPCR Signaling by Cryo-EM. Trends in Cell Biology, doi.org/10.1016/j.tcb.2018.06.002. [Trends In Cell Biology:]


Analysis of shared heritability in common disorders of the brain
(1) Brainstorm Consortium (2018). Analysis of shared heritability in common disorders of the brain. Science, 360(6395). pii: eaap8757. doi: 10.1126/science.aap8757. [PMID:]


Exploring Drugbank in Virtual Reality Chemical Space
(1) Probst D & Reymond J-L (2018). Exploring Drugbank in Virtual Reality Chemical Space. Science, doi.org/10.26434/chemrxiv.6629150.v1. [ChemRxiv:]


In vivo brain GPCR signaling elucidated by phosphoproteomics
(1) Liu JJ et al. (2018). In vivo brain GPCR signaling elucidated by phosphoproteomics. Science, 360(6395). pii: eaao4927. doi: 10.1126/science.aao4927. [PMID:]


Recommendations toward a human pathway-based approach to disease research
(1) Marshall LJ et al. (2018). Recommendations toward a human pathway-based approach to disease research. Drug Discov Today, pii: S1359-6446(17)30473-7. doi: 10.1016/j.drudis.2018.05.038. [Epub ahead of print]. [PMID:]


Defining Inflammatory Cell States in Rheumatoid Arthritis Joint Synovial Tissues by Integrating Single-cell Transcriptomics and Mass Cytometry
(1) Zhang F et al. (2018). Defining Inflammatory Cell States in Rheumatoid Arthritis Joint Synovial Tissues by Integrating Single-cell Transcriptomics and Mass Cytometry. BioRxiv, doi.org/10.1101/351130. [bioRxiv:]




Comments by Eamonn Kelly & Katy Sutcliffe, University of Bristol

Every few years in the field of receptor pharmacology, a technological advance occurs that drives the field forward in terms of insight and understanding. Over the past couple of years, the cryo-EM technique (the development of which won the 2017 Nobel Prize in Chemistry for Dubochet, Frank, and Henderson) for resolving protein structures at near atomic resolution has been highlighted as one such approach. Now some of the first papers applying this methodology to G protein-coupled receptors (GPCRs) are beginning to appear

(1) Garcia-Nafria J et al. (2018). Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric Go. Nature, 558(7711):620-623. doi: 10.1038/s41586-018-0241-9. [PMID:]




Comments by Steve Watterson, University of Ulster, ()

What will Systems Biology look like in the future? Up to now, it has focussed on the development of standards, software tools and databases that enabled us to study the dynamics of physiological function mechanistically. However as these tools and technologies have matured, the focus of the systems biology research community has moved towards how they can best be interconnected and exploited to develop our understanding of health and disease across whole cells, tissues, organs, organisms. This version 2.0 of systems biology, will build on the existing technologies to create resources that are more intuitive, more accurate, more accessible and are easier to use for anyone engaged with research.

(1) Mazein M et al. (2018). Systems medicine disease maps: community-driven comprehensive representation of disease mechanisms. NPJ Syst Biol Appl., 4:21. doi: 10.1038/s41540-018-0059-y. eCollection 2018. [PMID:]


Immune-centric network of cytokines and cells in disease context identified by computational mining of PubMed
(1) Kveler K et al. (2018). Immune-centric network of cytokines and cells in disease context identified by computational mining of PubMed. Nat Biotechnol., doi: 10.1038/nbt.4152. [Epub ahead of print]. [PMID:]


Crystal structure of the µ-opioid receptor bound to a morphinan antagonist
(1) Manglik A et al. (2018). Crystal structure of the µ-opioid receptor bound to a morphinan antagonist. Nature, 485(7398):321-6. doi: 10.1038/nature10954. [PMID:]


Emerging Approaches for the Identification of Protein Targets of Small Molecules - A Practitioners' Perspective
(1) Comess KM et al. (2018). Emerging Approaches for the Identification of Protein Targets of Small Molecules - A Practitioners' Perspective. J Med Chem, doi: 10.1021/acs.jmedchem.7b01921. [Epub ahead of print]. [PMID:]


Targeted protein degradation and the enzymology of degraders
(1) Fischer SL & Phillips AJ (2018). Targeted protein degradation and the enzymology of degraders. Curr Opin Chem Biol, 44:47-55. doi: 10.1016/j.cbpa.2018.05.004. [Epub ahead of print]. [PMID:]


The Assay Guidance Manual: Quantitative Biology and Pharmacology in Preclinical Drug Discovery
(1) Coussens NP et al. (2018). The Assay Guidance Manual: Quantitative Biology and Pharmacology in Preclinical Drug Discovery. Clin Transl Sci, doi: 10.1111/cts.12570. [Epub ahead of print]. [PMID:]


Cryo-EM in drug discovery: achievements, limitations and prospects
(1) Renaud JP et al. (2018). Cryo-EM in drug discovery: achievements, limitations and prospects. Nat Rev Drug Discov, doi: 10.1038/nrd.2018.77. [Epub ahead of print]. [PMID:]


Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice
(1) Que X et al. (2018). Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice. Nature, doi: 10.1038/s41586-018-0198-8. [Epub ahead of print]. [PMID:]


Genomic atlas of the human plasma proteome
(1) Sun BB et al. (2018). Genomic atlas of the human plasma proteome. Nature, 558(7708):73-79. doi: 10.1038/s41586-018-0175-2. [PMID:]


Clinical trial design and dissemination: comprehensive analysis of clinicaltrials.gov and PubMed data since 2005
(1) Zwierzyna M et al. (2018). Clinical trial design and dissemination: comprehensive analysis of clinicaltrials.gov and PubMed data since 2005. BMJ, doi: 10.1136/bmj.k2130. [BMJ:]


From genome-wide associations to candidate causal variants by statistical fine-mapping
(1) Schaid DJ, Chen W & Larson NB. (2018). From genome-wide associations to candidate causal variants by statistical fine-mapping. Nat Rev Genet, doi: 10.1038/s41576-018-0016-z. [Epub ahead of print]. [PMID:]


New Modalities, Technologies, and Partnerships in Probe and Lead Generation: enabling a Mode-of-Action centric paradigm
(1) Valuer E & Jimonet P. (2018). New Modalities, Technologies, and Partnerships in Probe and Lead Generation: enabling a Mode-of-Action centric paradigm. J Med Chem, doi: 10.1021/acs.jmedchem.8b00378. [Epub ahead of print]. [PMID:]


How artificial intelligence is changing drug discovery
(1) Fleming N. (2018). How artificial intelligence is changing drug discovery. Nature, 557(7707):S55-S57. doi: 10.1038/d41586-018-05267-x. [PMID:]


A big data approach to the concordance of the toxicity of pharmaceuticals in animals and humans
(1) Clark M & Steger-Hartmann T. (2018). A big data approach to the concordance of the toxicity of pharmaceuticals in animals and humans. Regul Toxicol Pharmacol, 96:94-105. doi: 10.1016/j.yrtph.2018.04.018. [PMID:]


25 Years of Molecular Biology Databases: A Study of Proliferation, Impact, and Maintenance
(1) Imker HJ. (2018). 25 Years of Molecular Biology Databases: A Study of Proliferation, Impact, and Maintenance. Front. Res. Metr. Anal, doi: 10.3389/frma.2018.00018. []


CypReact: A Software Tool for in Silico Reactant Prediction for Human Cytochrome P450 Enzymes
(1) Tian S et al. (2018). CypReact: A Software Tool for in Silico Reactant Prediction for Human Cytochrome P450 Enzymes. Future Med Chem, doi: 10.1021/acs.jcim.8b00035. [Epub ahead of print]. [PMID:]


Advocating for mutually beneficial access to shelved compounds
(1) Pulley JM et al. (2018). Advocating for mutually beneficial access to shelved compounds. Future Med Chem, doi: 10.4155/fmc-2018-0090. [Epub ahead of print]. [PMID:]


Structural basis for signal recognition and transduction by platelet-activating-factor receptor
(1) Cao C et al. (2018). Structural basis for signal recognition and transduction by platelet-activating-factor receptor. Nat Struc Mol Biol, 25(6):488-495. doi: 10.1038/s41594-018-0068-y. [PMID:]


Integrating rare genetic variants into pharmacogenetic drug response predictions
(1) Ingelman-Sundberg M et al. (2018). Integrating rare genetic variants into pharmacogenetic drug response predictions. Hum Genomics, 12(1):26. doi: 10.1186/s40246-018-0157-3. [PMID:]


May 2018

Reciprocal signalling by Notch–Collagen V–CALCR retains muscle stem cells in their niche
(1) Baghdadi MB et al. (2018). Reciprocal signalling by Notch–Collagen V–CALCR retains muscle stem cells in their niche. Nature, doi: 10.1038/s41586-018-0144-9. [Nature:]


The Cellosaurus, a Cell-Line Knowledge Resource
(1) Bairoch A. (2018). The Cellosaurus, a Cell-Line Knowledge Resource. J Biomol Tech., doi: 10.7171/jbt.18-2902-002 [Epub ahead of print]. [PMC:]


Genomic, Proteomic and Phenotypic Heterogeneity in HeLa Cells across Laboratories: Implications for Reproducibility of Research Results
(1) Liu Y et al. (2018). Genomic, Proteomic and Phenotypic Heterogeneity in HeLa Cells across Laboratories: Implications for Reproducibility of Research Results. bioRxiv., doi: 10.1101/307421. [bioRxiv:]


Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism
(1) Lancaster GI et al. (2018). Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism. Cell Metab., 27(5):1096-1110.e5. doi: 10.1016/j.cmet.2018.03.014. [PMID:]


A Census of Disease Ontologies
(1) Haendel M et al. (2018). A Census of Disease Ontologies. Annual Reviews, doi: 10.1146/annurev-biodatasci-080917-013459. []


Drugs as habitable planets in the space of dark chemical matter
(1) Siramshetty VB & Preissner R. (2018). Drugs as habitable planets in the space of dark chemical matter. Drug Discov Today, 23(3):481-486. doi: 10.1016/j.drudis.2017.07.003. [PMID:]


Metabolism as a Target for Modulation in Autoimmune Diseases
(1) Huang N & Perl A. (2018). Metabolism as a Target for Modulation in Autoimmune Diseases. Trends Immunol., S1471-4906(18)30083-8. doi: 10.1016/j.it.2018.04.006. [Epub ahead of print]. [PMID:]


Activation mechanisms for a universal signalling protein
(1) Krumm B & Roth BL (2018). Activation mechanisms for a universal signalling protein. Nature News and Views. doi: 10.1038/d41586-018-04977-6. []




Comments by Steve Alexander, IUPHAR/BPS Meebo-online.info, ()

The A2A adenosine receptor is densely expressed in dopamine-rich areas of the brain and in the vasculature. It is the target of an adjunct medication for Parkinson’s Disease, istradefylline in Japan, an A2A receptor antagonist. The A2A adenosine receptor is an example of a Gs-coupled receptor, activation of which in the cardiovascular system leads to inhibition of platelet aggregation and vasorelaxation. This new report highlights the link between the receptor and the G protein to focus on areas of unexpected flexibility in the ligand binding region.

(1) Garcia-Nafría J et al. (2018). Cryo-EM structure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein. eLife, 7. pii: e35946. doi: 10.7554/eLife.35946. [PMID: ]


Emerging Paradigm of Intracellular Targeting of G Protein-Coupled Receptors
(1) Chaturvedi M et al. (2018). Emerging Paradigm of Intracellular Targeting of G Protein-Coupled Receptors. Trends in Biomedical Sci., [Epub ahead of print]. doi: 10.1016/j.tibs.2018.04.003. []


Pharma’s broken business model — Part 2: Scraping the barrel in drug discovery
(1) Stott K (2018). IDO inhibitors appear to have wiped out. Endpoint News - Biotech Voices, 2nd May 2018. []


Pharma’s broken business model Part 1: An industry on the brink of terminal decline
(1) Stott K (2017). Pharma’s broken business model Part 1: An industry on the brink of terminal decline. Endpoint News - Biotech Voices, 28th Nov 2017. []


Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis
(1) Zhang M et al. (2018). Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis. Science, 360(6388): pii: eaap7847. doi: 10.1126/science.aap7847. [PMID:]




Comments by Chris Southan, IUPHAR/BPS Meebo-online.info, ()

BACE1 (beta secretase 1, BACE-1 or BACE) has been a key target for Alzheimer's disease (AD) for nearly two decades (1).  However, there was a major disappointment when the Phase III trials with the Merck inhibitor verubecestat failed unequivocally despite lowering A-beta levels.  The termination is reported both in   and the  May 2018  full paper on the trial results (2).

(1) Egan MF et al. (2018). Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease. N Engl J Med., 378(18):1691-1703. doi: 10.1056/NEJMoa1706441. [PMID:]




Comments by Steve Alexander, IUPHAR/BPS Meebo-online.info, ()

The TRPV2 ion channel is the less well-characterised relative of the TRPV1 or vanilloid receptor that is activated by capsaicin. TRPV2 channels have many similarities to the TRPV1 channels, in that they are homotetrameric and respond to some of the same ligands (natural products such as cannabinoids) as well as being triggered at elevated temperatures. This study (1) focusses on a different common feature of the whole Transient Receptor Potential family, which are often described as non-selective cation channels.

(1) Zubcevic L et al. (2018). Conformational plasticity in the selectivity filter of the TRPV2 ion channel. Nat Struc Mol Biol., 25:405-415. doi:10.1038/s41594-018-0059-z. []


IDO inhibitors appear to have wiped out
(1) Lowe D (2018). IDO inhibitors appear to have wiped out. STM: In The Pipeline, 1st May 2018. []


A TRP channel trio mediates acute noxious heat sensing
(1) Vandewauw I et al. (2018). A TRP channel trio mediates acute noxious heat sensing. Nature, 555(7698):662-666. doi: 10.1038/nature26137. [PMID:]


A computationally driven analysis of the polyphenol-protein interactome
(1) Lacroix S et al. (2018). A computationally driven analysis of the polyphenol-protein interactome. Sci Rep., 8(1):2232. doi: 10.1038/s41598-018-20625-5. [PMID:]


April 2018

Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector
(1) Wang C et al. (2018). Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med., [Epub ahead or print]. doi: 10.1038/s41591-018-0004-z. [PMID:]


New Paradigms in Adenosine Receptor Pharmacology: Allostery, Oligomerization and Biased Agonism
(1) Vecchio EA et al. (2018). New Paradigms in Adenosine Receptor Pharmacology: Allostery, Oligomerization and Biased Agonism. Br J Pharmacol., [Epub ahead or print]. doi: 10.1111/bph.14337. [PMID:]


Cryo-EM structure of substrate-bound human telomerase holoenzyme
(1) Nguyen THD et al. (2018). Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nature, [Epub ahead or print]. doi: 10.1038/s41586-018-0062-x. [PMID:]


Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry
(1) Rizvi NF et al. (2018). Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry. ACS Chem Biol., 13(3):820-831. doi: 10.1021/acschembio.7b01013. [PMID:]


Structural basis for GPR40 allosteric agonism and incretin stimulation
(1) Ho JD et al. (2018). Structural basis for GPR40 allosteric agonism and incretin stimulation. Nat Commun., 9(1):1645. doi: 10.1038/s41467-017-01240-w. [PMID:]


Can we accelerate medicinal chemistry by augmenting the chemist with Big Data and artificial intelligence?
(1) Griffen EJ et al. (2018). Can we accelerate medicinal chemistry by augmenting the chemist with Big Data and artificial intelligence? Drug Discov Today, [Epub ahead of print] pii: S1359-6446(17)30578-0. doi: 10.1016/j.drudis.2018.03.011. [PMID:]


Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study
(1) DeBoever C et al. (2018). Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study. Nat Commun.,9(1):1612. doi: 10.1038/s41467-018-03910-9. [PMID:]


The 100 000 Genomes Project: bringing whole genome sequencing to the NHS
(1) Turnbull C et al.The 100 000 Genomes Project: bringing whole genome sequencing to the NHS. BMJ,361:k1687. doi: 10.1136/bmj.k1687. [PMID:]


Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease
(1) Emdin CA et al. (2018). Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease. Nat Commun.,9(1):1613. doi: 10.1038/s41467-018-03911-8. [PMID:]


Are there physicochemical differences between allosteric and competitive ligands?
(1) Smith RD, Lu J & Carlson HA (2018). Are there physicochemical differences between allosteric and competitive ligands?. PLoS, 13(11):e1005813. doi: 10.1371/journal.pcbi.1005813. [PMID:]


Redundancy in two major compound databases
(1) Yonchev D et al. (2018). Redundancy in two major compound databases. Drug Discov Today, [Epub ahead of print] pii: S1359-6446(18)30027-8. doi: 10.1016/j.drudis.2018.03.005. [PMID:]


Donated chemical probes for open science
(1) Müller S et al.(2018). Donated chemical probes for open science. eLife, 7. pii: e34311. doi: 10.7554/eLife.34311.. [PMID:]


PKIDB: A Curated, Annotated and Updated Database of Protein Kinase Inhibitors in Clinical Trials
(1) Carles F. et al.. (2018). PKIDB: A Curated, Annotated and Updated Database of Protein Kinase Inhibitors in Clinical Trials. Molecules, 23(4). pii: E908. doi: 10.3390/molecules23040908. [PMID:]


Translating translation
(1) Austin CP. (2018). Translating translation. Nat Rev Drug Discov., [Epub ahead of print]. doi: 10.1038/nrd.2018.27. [PMID:]




Comments by Dr. Charles Kennedy, University of Strathclyde

Negative allosteric modulators (NAMs) are of great interest in drug development because they offer improved scope for the production of receptor antagonists with enhanced subtype-selectivity. Indeed, many NAMs are already on the market or undergoing clinical trials. NAMs act by binding to sites within receptors that are distinct from the primary, orthosteric ligand binding site and can inhibit the structural rearrangements of a receptor that are induced by orthosteric agonist binding. P2X receptors are ligand-gated cation channels for which ATP is the endogenous orthosteric agonist. They are expressed throughout the body and the evidence indicates that they have numerous functions, including in sympathetic and parasympathetic neurotransmission, perception of sound, taste and pain, and immune regulation. Seven P2X subunits have been identified, which form trimers, to produce at least twelve different receptor subtypes. A major issue within the field has been a lack of selective antagonists for most P2X subtypes. This is unsurprising given the amino acid sequence similarity within the ATP binding site. Several selective NAMs have now been developed, but little is known about where in receptors they act and how exactly they inhibit receptor activation. AF-219 is small molecule NAM at P2X3 receptors that was reported to be effective in a phase II clinical trial for treatment of refractory chronic cough. Wang et al., (1) combined X-ray crystallography, molecular modelling, and mutagenesis, to identify the site and mode of action of AF-219. P2X3 receptors are composed of three subunits, each of which adopts a conformation that could be likened to the shape of a leaping dolphin.

(1) Wang J et al. (2018). Druggable negative allosteric site of P2X3 receptors. Proc Natl Acad Sci USA, [Epub ahead of print] pii: 201800907. doi: 10.1073/pnas.1800907115. [PMID:]


Observing the cell in its native state: Imaging subcellular dynamics in multicellular organisms
(1) Liu TL et al. (2018). Observing the cell in its native state: Imaging subcellular dynamics in multicellular organisms. Science, 360(6386):762-775. pii: eaaq1392. doi: 10.1126/science.aaq1392. [PMID:]


GPR68 Senses Flow and Is Essential for Vascular Physiology
(1) Xu J et al. (2018). GPR68 Senses Flow and Is Essential for Vascular Physiology. Cell, 173(3):762-775. doi: 10.1016/j.cell.2018.03.076. [PMID:]


Challenges in validating candidate therapeutic targets in cancer
(1) Settleman J, Sawyers CL & Hunter T (2018). Challenges in validating candidate therapeutic targets in cancer. eLife, 7. pii: e32402. doi: 10.7554/eLife.32402. [PMID:]


Of mice, men and immunity: a case for evolutionary systems biology
(1) Ernst PB & Carvunis AR (2018). Of mice, men and immunity: a case for evolutionary systems biology. Nat Immunol., 19(5):421-425. doi: 10.1038/s41590-018-0084-4. [PMID:]


High-Throughput Gene Expression Profiles to Define Drug Similarity and Predict Compound Activity
(1) De Wolf H et al. (2018). High-Throughput Gene Expression Profiles to Define Drug Similarity and Predict Compound Activity. Assay Drug Dev Technol., 16(3):162-176. doi: 10.1089/adt.2018.845. [PMID:]


Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor
(1) Yang Z et al. (2018). Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor. Nature, 556(7702):520-524. doi: 10.1038/s41586-018-0046-x. [PMID:]


Untangling Galectin-Driven Regulatory Circuits in Autoimmune Inflammation
(1) Toscano MA et al. (2018). Untangling Galectin-Driven Regulatory Circuits in Autoimmune Inflammation. Trends Mol Med., 24(4):348-363. doi: 10.1016/j.molmed.2018.02.008. [PMID:]


Biocuration: Distilling data into knowledge
(1) International Society for Biocuration. (2018). Biocuration: Distilling data into knowledge. PLoS Biol., 16(4):e2002846. doi: 10.1371/journal.pbio.2002846. [PMID:]


Interleukins and their signaling pathways in the Reactome biological pathway database
(1) Jupe S et al. (2018). Interleukins and their signaling pathways in the Reactome biological pathway database. J Allergy Clin Immunol., 141(4):1411-1416. doi: 10.1016/j.jaci.2017.12.992. [PMID:]


Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements
(1) Hudson WH et al. (2018). Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements. Nat Commun., 9(1):1337. doi: 10.1038/s41467-018-03780-1. [PMID:]


Identification of rare sequence variation underlying heritable pulmonary arterial hypertension
(1) Gräf S et al. (2018). Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nat Commun., 9(1):1416. doi: 10.1038/s41467-018-03672-4. [PMID:]


Accessing Expert‐Curated Pharmacological Data in the IUPHAR/BPS Meebo-online.info
(1) Sharman JL et al. (2018). Accessing Expert‐Curated Pharmacological Data in the IUPHAR/BPS Meebo-online.info. Curr Prot in Bionfomatics., 61(1):1.34.1-1.34.46. doi: 10.1002/cpbi.46. []


Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity
(1) Pao KC et al. (2018). Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity. Nature, 556(7701):381-385. doi: 10.1038/s41586-018-0026-1. [PMID:]


Innate immune memory in the brain shapes neurological disease hallmarks
(1) Wendeln AC et al. (2018). Innate immune memory in the brain shapes neurological disease hallmarks. Nature, 556(7701):332-328. doi: 10.1038/s41586-018-0023-4. [PMID:]


Meta-analysis of genetic association with diagnosed Alzheimer's disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing
(1) Kunkle BW et al. (2018). Meta-analysis of genetic association with diagnosed Alzheimer's disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing. bioRxiv. doi: 10.1101/294629. []


Chemical probes and drug leads from advances in synthetic planning and methodology
(1) Gerry CJ & Schreiber SL. (2018). Chemical probes and drug leads from advances in synthetic planning and methodology. Nat Rev Drug Discov., 17(5):333-352. doi: 10.1038/nrd.2018.53. [PMID:]


The Proposal to Lower P Value Thresholds to .005.
(1) Ioannidis JPA. (2018). The Proposal to Lower P Value Thresholds to .005. JAMA, 319(14):1429-1430. doi: 10.1001/jama.2018.1536. [PMID:]


A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations
(1) Litichevskiy L et al. (2018). A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations. Cell Syst., 6(4):424-443. doi: 10.1016/j.cels.2018.03.012. [PMID:]


High-throughput mouse phenomics for characterizing mammalian gene function
(1) Brown SDM et al. (2018). High-throughput mouse phenomics for characterizing mammalian gene function. Nat Rev Genet., [Epub ahead of print]. doi: 10.1038/s41576-018-0005-2. [PMID:]


Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
(1) Mahajan A et al. (2018). Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. Nat Genet., 50(4):559-571. doi: 10.1038/s41588-018-0084-1. [PMID:]


Analysis of Human Sequence Data Reveals Two Pulses of Archaic Denisovan Admixture
(1) Browning SR et al. (2018). Analysis of Human Sequence Data Reveals Two Pulses of Archaic Denisovan Admixture. Cell, 173(1):53-61. doi: 10.1016/j.cell.2018.02.031. [PMID:]


Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis
(1) Scapin G et al. (2018). Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis. Nature, 556(7699):122-125. doi: 10.1038/nature26153. [PMID:]


Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses
(1) Ballard A et al. (2018). Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses. Angew Chem Int Ed Engl., 57(4):982-985. doi: 10.1002/anie.201709163. [PMID:]


Searching and Extracting Data from the EMBL-EBI Complex Portal
(1) Meldal BHM, Orchard S. (2018). Searching and Extracting Data from the EMBL-EBI Complex Portal. Methods Mol Biol., 1764:377-390. doi: 10.1007/978-1-4939-7759-8_24. [PMID:]


Accurate functional classification of thousands of BRCA1 variants with saturation genome editing
(1) Findlay GM et al. (2018). Accurate functional classification of thousands of BRCA1 variants with saturation genome editing. BioRxiv, doi: 10.1101/294520. [Epub ahead of print] []


Opportunities and obstacles for deep learning in biology and medicine
(1) Ching T et al. (2018). Opportunities and obstacles for deep learning in biology and medicine. J R Soc Interface., 15(141). pii: 20170387. doi: 10.1098/rsif.2017.0387. [PMID:]


The Immune Landscape of Cancer
(1) Thorsson V et al. (2018). The Immune Landscape of Cancer. Immunity, doi: 10.1016/j.immuni.2018.03.023. [Epub ahead of print] []


Disease-Causing Mutations in the G Protein Gαs Subvert the Roles of GDP and GTP
(1) Hu Q, Shokat KM. (2018). Disease-Causing Mutations in the G Protein Gαs Subvert the Roles of GDP and GTP. Cell, doi: 10.1016/j.cell.2018.03.018. [Epub ahead of print] []


Identification of Misclassified ClinVar Variants via Disease Population Prevalence
(1) Shah N et al. (2018). Identification of Misclassified ClinVar Variants via Disease Population Prevalence. Am J Hum Genet., 102(4):609-619. doi: 10.1016/j.ajhg.2018.02.019. [PMID:]


Chemical Diversity in the G Protein-Coupled Receptor Superfamily
(1) Vass M et al. (2018). Chemical Diversity in the G Protein-Coupled Receptor Superfamily. Trends Pharmacol Sci., pii: S0165-6147(18)30035-X. doi: 10.1016/j.tips.2018.02.004. [Epub ahead of print] [PMID:]


Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology
(1) Hauwert NJ et al. (2018). Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology. J Am Chem Soc., 140(12):4232-4243. doi: 10.1021/jacs.7b11422. [PMID:]


Cross-disorder analysis of schizophrenia and 19 immune diseases reveals genetic correlation
(1) Pouget JG, et al. (2018). Cross-disorder analysis of schizophrenia and 19 immune diseases reveals genetic correlation. BioRxiv, doi: 10.1101/068684. [Epub ahead of print] []


Planning chemical syntheses with deep neural networks and symbolic AI
(1) Segler MHS et al. (2018). Planning chemical syntheses with deep neural networks and symbolic AI. Nature, 555(7698):604-610. doi: 10.1038/nature25978. [PMID:]


Biased signalling: from simple switches to allosteric microprocessors
(1) Smith JS et al. (2018). Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov, 17(4):243-260. doi: 10.1038/nrd.2017.229. [PMID:]


ImmPort, toward repurposing of open access immunological assay data for translational and clinical research
(1) Bhattacharya S et al. (2018). ImmPort, toward repurposing of open access immunological assay data for translational and clinical research. Sci Data, 5:180015. doi: 10.1038/sdata.2018.15. [PMID:]


Organic synthesis provides opportunities to transform drug discovery
(1) Blakemore DC et al. (2018). Organic synthesis provides opportunities to transform drug discovery. Nat Chem, 10(4):383-394. doi: 10.1038/s41557-018-0021-z. [PMID:]


March 2018



Comments by Stephan Kellenberger, Université de Lausanne, Switzerland

ASICs are potential drug targets of interest. Their activation mechanism has however remained elusive. ASICs are neuronal, proton-gated, sodium-permeable channels that are expressed in the central and peripheral nervous system of vertebrates. They form a subfamily of the Epithelial Na channel / degenerin channel family, and contribute to pain sensation, fear, learning, and neurodegeneration after ischemic stroke. Depending on the extracellular pH, they exist in either one of three functional states: closed (resting), open and desensitized. While ASICs are at physiological pH 7.4 in the closed state, they open briefly upon extracellular acidification, before entering the non-conducting desensitized state. Crystal structures of the chicken ASIC1 channel in the desensitized and the open state were published several years ago. This structural information allowed, together with observations from functional studies, an understanding of the transitions between the open and the desensitized state. In contrast, the absence of structural information on the closed conformation of ASICs precluded so far a molecular understanding of their activation mechanism.

The Gouaux laboratory has now published structures of the homotrimeric chicken ASIC1 obtained at high pH by X-ray crystallography (2.95 Å resolution) and by single particle cryo-electron microscopy (3.7 Å) (1).

(1) Yoder N et al. (2018). Gating mechanisms of acid-sensing ion channels. Nature, 555(7696):397-401. doi: 10.1038/nature25782. [PMID:]


Extensive impact of non-antibiotic drugs on human gut bacteria
(1) Maier L, et al. (2018). Extensive impact of non-antibiotic drugs on human gut bacteria. Nature, doi:10.1038/nature25979. [Epub ahead of print] []


A Machine Learning Approach Predicts Tissue-Specific Drug Adverse Events
(1) Madhukar NS, et al. (2018). A Machine Learning Approach Predicts Tissue-Specific Drug Adverse Events. BioRxiv, doi: 10.1101/288332. [Epub ahead of print] []


Ranking Enzyme Structures in the PDB by Bound Ligand Similarity to Biological Substrates
(1) Tyzack JD et al. (2018). Ranking Enzyme Structures in the PDB by Bound Ligand Similarity to Biological Substrates. Structure, pii: S0969-2126(18)30049-2. doi: 10.1016/j.str.2018.02.009. [Epub ahead of print] [PMID:]


Structural insights into the voltage and phospholipid activation of the mammalian TPC1 channel
(1) She J et al. (2018). Structural insights into the voltage and phospholipid activation of the mammalian TPC1 channel. Nature, doi: 10.1038/nature26139. [Epub ahead of print] [PMID:]


Conflicting evidence for the role of JNK as a target in breast cancer cell proliferation: Comparisons between pharmacological inhibition and selective shRNA knockdown approaches
(1) Wood RA et al. (2018). Conflicting evidence for the role of JNK as a target in breast cancer cell proliferation: Comparisons between pharmacological inhibition and selective shRNA knockdown approaches. Pharmacol Res Perspect., 6(1). doi: 10.1002/prp2.376. [PMID:]


Closely related, yet unique: Distinct homo- and heterodimerization patterns of G protein coupled chemokine receptors and their fine-tuning by cholesterol
(1) Gahbauer S et al. (2018). Closely related, yet unique: Distinct homo- and heterodimerization patterns of G protein coupled chemokine receptors and their fine-tuning by cholesterol. PLoS Comput Biol., 14(3):e1006062. doi: 10.1371/journal.pcbi.1006062. [PMID:]




Comments by Shane C. Wright and Gunnar Schulte, Karolinska Institute

In order to stabilize the GPCR-G protein complex, an agonist must be bound to the receptor and the alpha subunit of the heterotrimer must be in a nucleotide-free state. Ground-breaking work by expert crystallographers made use of so-called mini G (mG) proteins to stabilize the active conformation of the adenosine A2A receptor in the presence of agonist and guanine nucleotides, but in the absence of Gβγ [1]. These engineered G proteins behave in a way that mimics the nucleotide-free state despite being bound to GDP; thus, they can be seen as conformational sensors of the active receptor state. This work paved the way for another study recently published in the Journal of Biological Chemistry led by Nevin A. Lambert that looked to build on this minimalistic approach to see if representative mG proteins from the four subclasses (Gs, Gi/o, Gq/11 and G12/13) could 1) detect active GPCRs and 2) retain coupling specificity [2].

(1) Carpenter B et al. (2016) Structure of the adenosine A(2A) receptor bound to an engineered G protein. Nature, 536 (7614): 104-107. [PMID:]
(2) Wan Q et al. (2018) Mini G protein probes for active G protein-coupled receptors (GPCRs) in live cells. J Biol Chem. pii: jbc.RA118.001975. doi: 10.1074/jbc.RA118.001975. [Epub ahead of print] [PMID:]


Functionally distinct and selectively phosphorylated GPCR subpopulations co-exist in a single cell
(1) Shen A et al. (2018). Functionally distinct and selectively phosphorylated GPCR subpopulations co-exist in a single cell. Nat Commun., 9(1):1050. doi: 10.1038/s41467-018-03459-7. [PMID:]


Heterologous Expression, Biosynthetic Studies, and Ecological Function of the Selective Gq-Signaling Inhibitor FR900359
(1) Crüsemann M et al. (2018). Heterologous Expression, Biosynthetic Studies, and Ecological Function of the Selective Gq-Signaling Inhibitor FR900359. Angew Chem Int Ed Engl., 57(3):836-840. doi: 10.1002/anie.201707996. [PMID:]


A comprehensive and quantitative comparison of text-mining in 15 million full-text articles versus their corresponding abstracts
(1) Westergaard D et al. (2018). A comprehensive and quantitative comparison of text-mining in 15 million full-text articles versus their corresponding abstracts. PLoS Comput Biol., 4(2):e1005962. doi: 10.1371/journal.pcbi.1005962. [PMID:]


Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults
(1) Perkins BA et al. (2018). Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults. Proc Natl Acad Sci U S A., pii: 201706096. doi: 10.1073/pnas.1706096114. [Epub ahead of print] [PMID:]


Crystal structure of the human 5-HT1B serotonin receptor bound to an inverse agonist
(1) Yin W et al. (2018). Crystal structure of the human 5-HT1B serotonin receptor bound to an inverse agonist. Cell Discovery, 4. doi:10.1038/s41421-018-0009-2. [Epub ahead of print] []


Augmented Reality in Scientific Publications-Taking the Visualization of 3D Structures to the Next Level
(1) Wolle P et al. (2018). Augmented Reality in Scientific Publications-Taking the Visualization of 3D Structures to the Next Level. ACS Chem Biol., 13(3):496-499. doi: 10.1021/acschembio.8b00153. [PMID:]


Exploring G Protein-Coupled Receptors (GPCRs) Ligand Space via Cheminformatics Approaches: Impact on Rational Drug Design
(1) Basith S et al. (2018). Exploring G Protein-Coupled Receptors (GPCRs) Ligand Space via Cheminformatics Approaches: Impact on Rational Drug Design. Frontiers in Pharmacology, doi:10.3389/fphar.2018.00128. [Epub ahead of print] []


WhichP450: a multi-class categorical model to predict the major metabolising CYP450 isoform for a compound
(1) Hunt PA et al. (2018). WhichP450: a multi-class categorical model to predict the major metabolising CYP450 isoform for a compound. J Comput Aided Mol Des., doi: 10.1007/s10822-018-0107-0. [Epub ahead of print] [PMID:]


Validation of ligands in macromolecular structures determined by X-ray crystallography
(1) Smart OS et al. (2018). Validation of ligands in macromolecular structures determined by X-ray crystallography. Acta Crystallogr D Struct Biol., 74(Pt 3):228-236. doi: 10.1107/S2059798318002541. [PMID:]


Translational Bioinformatics year in review 2018
(1) Altman R. (2018). []


Pharma R&D Annual Review 2018
(1) Lloyd I. (2018). []


Small Molecule Interactome Mapping by Photoaffinity Labeling Reveals Binding Site Hotspots for the NSAIDs
(1) Gao J et al. (2018). Small Molecule Interactome Mapping by Photoaffinity Labeling Reveals Binding Site Hotspots for the NSAIDs. J Am Chem Soc., doi: 10.1021/jacs.7b11639. [Epub ahead of print] [PMID:]


Kinase inhibitors: the road ahead
(1) Ferguson FM, Gray NS. (2018). Kinase inhibitors: the road ahead. Nat Rev Drug Discov., doi: 10.1038/nrd.2018.21. [Epub ahead of print] [PMID:]


STRENDA DB: enabling the validation and sharing of enzyme kinetics data
(1) Swainston N et al. (2018). STRENDA DB: enabling the validation and sharing of enzyme kinetics data. FEBS J., doi: 10.1111/febs.14427. [Epub ahead of print] [PMID:]


Genetic risk for Alzheimer's disease is concentrated in specific macrophage and microglial transcriptional networks
(1) Tansey KE et al. (2018). Genetic risk for Alzheimer's disease is concentrated in specific macrophage and microglial transcriptional networks. Genome Med., 10(1):14. doi: 10.1186/s13073-018-0523-8. [PMID:]


Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug-Target Interactions
(1) Lu S, Zhang J. (2018). Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug-Target Interactions. J Med Chem, doi: 10.1021/acs.jmedchem.7b01844. [Epub ahead of print] [PMID:]




Comments by Chris Southan, IUPHAR/BPS Meebo-online.info,

Contemporary drug discovery is dominated by two related themes. The first of these is target validation upon which the sustainability of pharmaceutical R&D (in both the commercial and academic sectors) crucially depends. The second is the size of the pool of human proteins that are/could become tractable to being progressed towards clinical efficacy as their final validation step (otherwise known as the druggable proteome). This usefully detailed review, by a large team of authors, touches on both themes but with a focus on how the community might increase the target pool by data-driven knowledge expansion for hitherto less well characterised proteins [1].

(1) Oprea TI et al. (2018). Unexplored therapeutic opportunities in the human genome. Nat Rev Drug Discov. doi: 10.1038/nrd.2018.14 [Epub ahead of print] [PMID:]


Prevalence of clinical trial status discrepancies: A cross-sectional study of 10,492 trials registered on both ClinicalTrials.gov and the European Union Clinical Trials Register
(1) Fleminger J, Goldacre B. (2018). Prevalence of clinical trial status discrepancies: A cross-sectional study of 10,492 trials registered on both ClinicalTrials.gov and the European Union Clinical Trials Register. PLoS One, 13(3):e0193088. doi: 10.1371/journal.pone.0193088. [PMID:]


An Augmented Pocketome: Detection and Analysis of Small-Molecule Binding Pockets in Proteins of Known 3D Structure
(1) Bhagavat R et al. (2018). An Augmented Pocketome: Detection and Analysis of Small-Molecule Binding Pockets in Proteins of Known 3D Structure. Structure, 26(3):499-512.e2. doi: 10.1016/j.str.2018.02.001. [PMID:]


Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms
(1) Deng Z et al. (2018). Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms. Nat Struct Mol Biol., 25(3):252-260. doi: 10.1038/s41594-018-0037-5. [PMID:]


The role of gut microbiome and associated metabolome in the regulation of neuroinflammation in multiple sclerosis and its implications in attenuating chronic inflammation in other inflammatory and autoimmune disorders
(1) Dopkins N, Nagarkatti PS, Nagarkatti M. (2018). The role of gut microbiome and associated metabolome in the regulation of neuroinflammation in multiple sclerosis and its implications in attenuating chronic inflammation in other inflammatory and autoimmune disorders. Immunology, doi: 10.1111/imm.12903. [Epub ahead of print] [PMID:]


The rise of deep learning in drug discovery
(1) Chen H et al. (2018). The rise of deep learning in drug discovery. Drug Discov Today, pii: S1359-6446(17)30359-8. doi: 10.1016/j.drudis.2018.01.039. [Epub ahead of print] [PMID:]


Big Data in Drug Discovery
(1) Brown N et al. (2018). Big Data in Drug Discovery. Progress in Medicinal Chemistry, doi:10.1016/bs.pmch.2017.12.003. [Epub ahead of print] []


February 2018



Comments by Julien Hanson, University of Liege

This paper (1) sheds some light on the current state of the field and the phenomenon of reduced discoveries in the orphan landscape. Although it is true that fewer deorphanizations have been reported recently compared to the 1990-2000 period, the authors propose that the rate has reached a "steady-state" stage. Nevertheless, with more than 100 remaining orphans, the daunting task of full deorphanization that lies ahead will require creative approaches both at the technical and conceptual level.

(1) Laschet C, Dupuis N, Hanson J. (2018). The G Protein-Coupled Receptors deorphanization landscape. Biochem Pharmacol., pii: S0006-2952(18)30073-X. doi: 10.1016/j.bcp.2018.02.016. [Epub ahead of print] [PMID:]


Integrative omics for health and disease
(1) Karczewski KJ and Snyder MP. (2018). Integrative omics for health and disease. Nature Reviews Genetics, doi:10.1038/nrg.2018.4. [Epub ahead of print] []


Selective Photoaffinity Probe That Enables Assessment of Cannabinoid CB2 Receptor Expression and Ligand Engagement in Human Cells
(1) Soethoudt M et al. (2018). Selective Photoaffinity Probe That Enables Assessment of Cannabinoid CB2 Receptor Expression and Ligand Engagement in Human Cells. J Am Chem Soc., doi: 10.1021/jacs.7b11281. [Epub ahead of print] [PMID:]


Caveat usor: assessing differences between major chemistry databases
(1) Southan C. (2018). Caveat usor: assessing differences between major chemistry databases. ChemMedChem., doi: 10.1002/cmdc.201700724. [Epub ahead of print] [PMID:]


£54 million funding to transform UK health through data science
Health Data Research UK is awarding £30 million funding to six sites across the UK to address challenging healthcare issues through use of data science. Each site has world-class expertise; a track record in using health data to derive new knowledge, scientific discovery and insight; and works in close partnership with NHS bodies and the public to translate research findings into benefits for patients and populations. [Read more at ]


The 100,000 Genomes Project
The project will sequence 100,000 genomes from around 70,000 people. Participants are NHS patients with a rare disease, plus their families, and patients with cancer. [Read more at ]


BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology
(1) Peters F et al. (2018). BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology. Acta Neuropathol., doi: 10.1007/s00401-017-1804-9. [Epub ahead of print] [PMID:]


5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology
(1) Peng Y et al. (2018). 5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. Cell, 172(4):719-730.e14. doi: 10.1016/j.cell.2018.01.001. [PMID:]


Deubiquitylating enzymes and drug discovery: emerging opportunities
(1) Harrigan JA et al. (2018). Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat Rev Drug Discov., 17(1):57-78. doi: 10.1038/nrd.2017.152. [PMID:]


January 2018

Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone
(1) Wang S et al. (2018). Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone. Nature, doi:10.1038/nature25758. [Epub ahead of print]. []


The Enduring Legacy of 250 Years of Pharmacology in Edinburgh
(1) Kelly JS, Mackay AVP. (2018). The Enduring Legacy of 250 Years of Pharmacology in Edinburgh. Annu Rev Pharmacol Toxicol., 58:293-307. doi: 10.1146/annurev-pharmtox-010617-052901 [PMID:]


A Serendipitous Scientist
(1) Lefkowitz RJ. (2018). A Serendipitous Scientist. Annu Rev Pharmacol Toxicol., 58:17-32. doi: 10.1146/annurev-pharmtox-010617-053149. [PMID:]




Comments by Alexander Hauser, University of Copenhagen and GPCRdb

A collaboration between the MRC Laboratory of Molecular Biology, Cambridge (UK), the Scripps Research Institute in Florida and the Department of Drug Design and Pharmacology, University of Copenhagen (home of the GPCRdb team) has now published a new detailed study on the effects of genetic variation in G protein-coupled receptors on responses to FDA-approved drugs [1]. The authors address the following main questions: How variable are GPCR drug targets in the human population? Are individuals with variant receptors likely to respond differently to drugs? What is the estimated economic burden associated with variation in GPCR drug targets?

(1) Hauser AS et al. (2017). Pharmacogenomics of GPCR Drug Targets. Cell, 172(1-2):41-54.e19. doi:10.1016/j.cell.2017.11.033. [PMID:]


Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor
(1) Che T et al. (2018). Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor. Drug Discov Today, 172(1-2):55-67.e15. doi: 10.1016/j.cell.2017.12.011. [PMID:]


Drug target residence time: a misleading concept
(1) Folmer RHA. (2017). Drug target residence time: a misleading concept. Drug Discov Today, S1359-6446(17)30241-6. doi: 10.1016/j.drudis.2017.07.016. [PMID:]


GPCRs as targets for approved drugs: How many targets and how many drugs?
(1) Sriram K & Insel PA. (2018). GPCRs as targets for approved drugs: How many targets and how many drugs? Mol Pharmacol., doi: 10.1124/mol.117.111062. [Epub ahead of print]. [PMID:]


International Union of Basic and Clinical Pharmacology CIII
(1) Kennedy AJ & Davenport AP. (2018). International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin1) and GPR1 (Chemerin2) Nomenclature, Pharmacology, and Function. Pharmacol Rev., 70(1):174-196. doi: 10.1124/pr.116.013177. [PMID:]


Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727
(1) Roberston N et al. (2018). Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727. Nature, 553(7686):111-114 doi: 10.1038/nature25025. [PMID:]


Structure of the glucagon receptor in complex with a glucagon analogue
(1) Zhang H et al. (2018). Structure of the glucagon receptor in complex with a glucagon analogue. Nature, 553(7686):106-110. doi: 10.1038/nature25153. [PMID:]


Allosteric Coupling of Drug Binding and Intracellular Signaling in the A2A Adenosine Receptor
(1) Eddy MT et al. (2017). Allosteric Coupling of Drug Binding and Intracellular Signaling in the A2A Adenosine Receptor. Cell Chem Biol., 172(1-2):68-80.e12. doi: 10.1016/j.cell.2017.12.004. [PMID:]


Drug Target Commons: A Community Effort to Build a Consensus Knowledge Base for Drug-Target Interactions
(1) Tang J et al. (2017). Drug Target Commons: A Community Effort to Build a Consensus Knowledge Base for Drug-Target Interactions. Cell Chem Biol., S2451-9456(17)30426-9. doi: 10.1016/j.chembiol.2017.11.009. [PMID:]


A dynamic map for learning, communicating, navigating and improving therapeutic development
(1) Wagner J et al. (2017). A dynamic map for learning, communicating, navigating and improving therapeutic development. Nat Rev Drug Discov., [EPub ahead of print]. doi: 10.1038/nrd.2017.217. [PMID:]


Residue-Specific Peptide Modification: A Chemist's Guide
(1) deGruyter JN et al. (2017). Residue-Specific Peptide Modification: A Chemist's Guide. Biochemistry., 56(30):3863-3873. doi: 10.1021/acs.biochem.7b00536. [PMID:]


Phenome-wide association studies (PheWAS) across large "real-world data" population cohorts support drug target validation
(1) Diogo D et al. (2017). Phenome-wide association studies (PheWAS) across large "real-world data" population cohorts support drug target validation BioRxiv., doi: https://doi.org/10.1101/218875. []


The spectrum of T cell metabolism in health and disease.
(1) Bantug GR et al. (2017). The spectrum of T cell metabolism in health and disease. Nat Rev Immunol., 18(1):19-34. doi: 10.1038/nri.2017.99. [PMID:]


Genetic variation in human drug-related genes
(1) Schärfe CPI et al. (2017). Genetic variation in human drug-related genes. Genome Med., 9(1):117. doi: 10.1186/s13073-017-0502-5. [PMID:]


Complex Portal - A Unifying Protein Complex Database
(1) Meldal, B et al. (2017). Complex Portal - A Unifying Protein Complex Database. Genomics and Computational Biology, [S.l.], v. 4, n. 1, p. e100052, dec. 2017. ISSN 2365-7154. []


Archive of previous years

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