Hot topics in pharmacology

Recent publications of interest recommended by NC-IUPHAR

2019: Jan | Feb | Mar | Apr

2018: Jul | Aug | Sep | Oct | Nov | Dec

April 2019

Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens
(1) Behan FM et al. (2019). Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature, doi: 10.1038/s41586-019-1103-9. [PMID:30971826]


Structure and dynamics of the active human parathyroid hormone receptor-1
(1) Zhao LH et al. (2019). Structure and dynamics of the active human parathyroid hormone receptor-1. Science, 364(6436):148-153. doi: 10.1126/science.aav7942. [PMID:30975883]


Architecture and subunit arrangement of native AMPA receptors elucidated by cryo-EM
(1) Zhao Y et al. (2019). Architecture and subunit arrangement of native AMPA receptors elucidated by cryo-EM. Science, pii: eaaw8250. doi: 10.1126/science.aaw8250. [PMID:30975770]


Rapid Deorphanization of Human Olfactory Receptors in Yeast
(1) Yasi EA et al. (2019). Rapid Deorphanization of Human Olfactory Receptors in Yeast. Biochemistry, doi: 10.1021/acs.biochem.8b01208. [PMID:30977365]


March 2019

No Pain, and No Worries?
(1) Lowe D. (2019). In The Pipeline: No Pain, and No Worries?. Sci Trans Med, 29 March 2019. [In The Pipeline: Article]


Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity
(1) Habib AM et al. (2019). Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity. British Journal of Anaesthesia, https://doi.org/10.1016/j.bja.2019.02.019. [SciDirect: Abstract]


The past, present and future of anti-malarial medicines
(1) Tse EG et al. (2019). The past, present and future of anti-malarial medicines. Malar J, 22;18(1):93. doi: 10.1186/s12936-019-2724-z. [PMID:30902052]


Biology must develop herd immunity against bad-actor molecules
(1) Plemper RK & Cox RM. (2018). Biology must develop herd immunity against bad-actor molecules. PLoS Pathog, 14(6):e1007038. doi: 10.1371/journal.ppat.1007038. [PMID:29953540]


Rise up against statistical significance, probably.

Comments by Alistair Mathie (@AlistairMathie), The Medway School of Pharmacy

A recent commentary in Nature has the provocative title “Retire Statistical Significance” [1 with a list of more than 800 signatories] and has been widely interpreted as a call for the entire concept of statistical significance to be abandoned. Closer reading of the commentary suggests that the main message of the paper is a call to stop the use of p values or confidence intervals in a categorical or binary sense in order to be absolute as to whether a result supports or refutes a scientific hypothesis. This remains a radical proposal but perhaps does not signal the end for statistical tests in biomedical research just yet. Read the full article on our blog

(1) Amrhein V, Greenland S & McShane B. (2019). Scientists rise up against statistical significance. Nature, 567(7748):305-307. doi: 10.1038/d41586-019-00857-9. [PMID:30894741]

(2) Curtis MJ et al. (2019). Experimental design and analysis and their reporting: new guidance for publication in BJP. Br J Pharmacol, 172(14):3461-71. doi: 10.1111/bph.12856. [PMID:26114403]

(3) Curtis MJ et al. (2019). Experimental design and analysis and their reporting II: updated and simplified guidance for authors and peer reviewers. Br J Pharmacol, 175(7):987-993. doi: 10.1111/bph.14153. [PMID:29520785]

(4) Colquhoun D. (2019). An investigation of the false discovery rate and the misinterpretation of p-values. R Soc Open Sci, 1(3):140216. doi: 10.1098/rsos.140216. eCollection 2014 Nov. [PMID:26064558]

(5) Casadevall A. (2019). Duke University’s huge misconduct fine is a reminder to reward rigour. Nature, 568(7). [World View: Article]


A Brief Note About Alzheimer’s
(1) Lowe D. (2019). In The Pipeline: A Brief Note About Alzheimer’s. Sci Trans Med, 21 March 2019. [In The Pipeline: Article]


Pharma R&D Annual Review 2018
(1) Lloyd I. (2019). Pharma R&D Annual Review 2018. Citeline. [Citeline:Whitepaper]


February 2019

Exciting Times for Ion Channel Pharmacology

Comments by Alistair Mathie (@AlistairMathie) and Emma L. Veale (@Ve11Emma), The Medway School of Pharmacy

Whilst life is always exciting as an ion channel pharmacologist, the last few months have been particularly so, with a large number of publications showing structures of ion channels with regulatory molecules bound to them. In just the last month, the journal, Science, has published several such papers. Three of these concern voltage-gated sodium channels (NaV1.2,, NaV1.7) and the binding of potent and selective toxins from animals [1-3]. Another reveals the structure of the primary human cooling and menthol sensor channel TRPM8 (id:500) bound to synthetic cooling and menthol-like compounds [4]. In the most recent paper [5], Schewe and colleagues extend their outstanding work on selectivity-filter gating of K2P potassium (K) channels (Schewe et al. (2016). Cell. PMID: 26919430), to identify a binding site for negatively charged activators of these channels (styled the “NCA binding site”) Read the full article on our blog

(1) Clairfeuille T et al. (2019). Structural basis of α-scorpion toxin action on Nav channels. Science, pii: eaav8573. doi: 10.1126/science.aav8573. [PMID:30733386]

(2) Shen H et al. (2019). Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins. Science, pii: eaaw2493. doi: 10.1126/science.aaw2493. [Epub ahead of print]. [PMID:30765606]

(3) Pan X et al. (2019). Molecular basis for pore blockade of human NaNa+ channel Nav1.2 by the μ-conotoxin KIIIA. Science, pii: eaaw2999. doi: 10.1126/science.aaw2999. [Epub ahead of print]. [PMID:30765605]

(4) Yin Y et al. (2019). Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel. Science, pii: eaav9334. doi: 10.1126/science.aav9334. [Epub ahead of print]. [PMID:30733385]

(5) Schewe M et al. (2019). A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels. Science, 363(6429):875-880. doi: 10.1126/science.aav0569.. [PMID:30792303]


Ligand biological activity predicted by cleaning positive and negative chemical correlations

Comments by Anthony Davenport, IUPHAR/BPS Guide to PHARMACOLOGY, University of Cambridge

New machine learning algorithm for drug discovery that is twice as efficient as the industry standard and identified potential ligands for the M1 receptor, a potential target for the treatment of Alzheimer’s disease [1]. Read the full article on our blog

(1) Lee AA et al. (2019). Ligand biological activity predicted by cleaning positive and negative chemical correlations. PNAS, https://doi.org/10.1073/pnas.1810847116. [Epub ahead of print]. [PNAS: Article]


Ligand biological activity predicted by cleaning positive and negative chemical correlations
(1) Lee AA et al. (2019). Ligand biological activity predicted by cleaning positive and negative chemical correlations. PNAS, https://doi.org/10.1073/pnas.1810847116. [Epub ahead of print]. [PNAS: Article]


Recent updates in the discovery and development of novel antimalarial drug candidates
(1) Okombo J & Chibale K (2019). Recent updates in the discovery and development of novel antimalarial drug candidates. MedChemComm, 9(3):437-453. doi: 10.1039/c7md00637c. [PMID:30108934]


A class of highly selective inhibitors bind to an active state of PI3Kγ
(1) Gangadhara G et al. (2019). A class of highly selective inhibitors bind to an active state of PI3Kγ. Nat Chem Biol, doi: 10.1038/s41589-018-0215-0. [Epub ahead of print]. [PMID:30718815]


3,3'-Disubstituted 5,5'-Bi(1,2,4-triazine) derivatives with Potent in vitro and in vivo Antimalarial Activity
(1) Xue L et al. (2019). 3,3'-Disubstituted 5,5'-Bi(1,2,4-triazine) derivatives with Potent in vitro and in vivo Antimalarial Activity. J Med Chem, doi: 10.1021/acs.jmedchem.8b01799. [Epub ahead of print]. [PMID:30715882]


Antibodies and venom peptides: new modalities for ion channels
(1) Cox MA et al. (2019). Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov, doi: 10.1038/s41573-019-0013-8. [Epub ahead of print]. [PMID:30728472]


Choline acetyltransferase-expressing T cells are required to control chronic viral infection
(1) Cox MA et al. (2019). Choline acetyltransferase-expressing T cells are required to control chronic viral infection. Science, 363(6427):639-644. doi: 10.1126/science.aau9072. [PMID:30733420]


Separating host and microbiome contributions to drug pharmacokinetics and toxicity
(1) Zimmermann M et al. (2019). Separating host and microbiome contributions to drug pharmacokinetics and toxicity. Science, 363(6427). pii: eaat9931. doi: 10.1126/science.aat9931. [PMID:30733391]


Diverse GPCRs exhibit conserved water networks for stabilization and activation
(1) Venkatakrishnan AJ et al. (2019). Diverse GPCRs exhibit conserved water networks for stabilization and activation. PNAS USA, pii: 201809251. doi: 10.1073/pnas.1809251116. [Epub ahead of print]. [PMID:30728297]


The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease
(1) Rothhammer V & Quintana FJ (2019). The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol, https://doi.org/10.1038/s41577-019-0125-8. [NatRevImmunol: Abstract]


Ca2+ allostery in PTH-receptor signaling
(1) White AD et al. (2019). Ca2+ allostery in PTH-receptor signaling. PNAS USA, pii: 201814670. doi: 10.1073/pnas.1814670116. [Epub ahead of print]. [PMID:30718391]


Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity
(1) Vriens K et al. (2019). Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity. Nat Struct Mol Biol, doi: 10.1038/s41586-019-0904-1. [Epub ahead of print]. [PMID:30728499]


Structures of the 5-HT2A receptor in complex with the antipsychotics risperidone and zotepine
(1) Kimura KT et al. (2019). Structures of the 5-HT2A receptor in complex with the antipsychotics risperidone and zotepine. Nat Struct Mol Biol, 26(2):121-128. doi: 10.1038/s41594-018-0180-z. [PMID:30723326]


January 2019

Global Portrait of Protein Targets of Metabolites of the Neurotoxic Compound BIA 10-2474
(1) Huang Z et al. (2019). Global Portrait of Protein Targets of Metabolites of the Neurotoxic Compound BIA 10-2474. ACS Chem Biol, doi: 10.1021/acschembio.8b01097. [Epub ahead of print]. [PMID:30702848]


Promises, promises, and precision medicine
(1) Joyner MJ & Paneth N (2019). Promises, promises, and precision medicine. J Clin Invest, pii: 126119. doi: 10.1172/JCI126119. [Epub ahead of print]. [PMID:30688663]


Pharmacological inhibition of GPR4 remediates intestinal inflammation in a mouse colitis model
(1) Sanderlin EJ et al. (2019). Pharmacological inhibition of GPR4 remediates intestinal inflammation in a mouse colitis model. bioRxiv, doi: https://doi.org/10.1101/533174. [bioRxiv:Abstract]


Navigating around Patented Routes by Preserving Specific Motifs along Computer-Planned Retrosynthetic Pathways
(1) Molga K et al. (2019). Navigating around Patented Routes by Preserving Specific Motifs along Computer-Planned Retrosynthetic Pathways. Chem, https://doi.org/10.1016/j.chempr.2018.12.004. [Chem in press:Article]


Hit Dexter 2.0: Machine-Learning Models for the Prediction of Frequent Hitters
(1) Stork C et al. (2019). Hit Dexter 2.0: Machine-Learning Models for the Prediction of Frequent Hitters. J Chem Inf Model, doi: 10.1021/acs.jcim.8b00677. [Epub ahead of print]. [PMID:30624935]


An online resource for GPCR structure determination and analysis

Comments by David E. Gloriam, University of Copenhagen (@David_Gloriam)

To accelerate the determination of GPCR structures and to help assess the quality of the available templates based on the modifications and methods, a recent article in Nature Methods presents “An Online Resource for GPCR Structure Determination and Analysis” [1]. Read the full article on our blog

(1) Munk C et al. (2019). An online resource for GPCR structure determination and analysis. J Med Chem, doi:10.1038/s41592-018-0302-x. [PMID:30664776]


Fatty acid recognition in the Frizzled receptor family
(1) Nile AH et al. (2019). Fatty acid recognition in the Frizzled receptor family. J Biol Chem, 294(2):726-736. doi: 10.1074/jbc.REV118.005205. [PMID:30530496]


Hydroxamic acid inhibitors provide cross-species inhibition of Plasmodium M1 and M17 aminopeptidases
(1) Vinh NB et al. (2019). Hydroxamic acid inhibitors provide cross-species inhibition of Plasmodium M1 and M17 aminopeptidases. J Med Chem, doi: 10.1021/acs.jmedchem.8b01310. [Epub ahead of print]. [PMID:30537832]


2018 New Drug Therapy Approvals
(1) Woodcock J (2019). 2018 New Drug Therapy Approvals. FDA. [PDF:Report]


Secreted amyloid-β precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission
(1) Rice HC et al. (2019). Secreted amyloid-β precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission. Science, 363(6423). pii: eaao5213. doi: 10.1126/science.aao5213. [PMID:30630900]


What Makes a Kinase Promiscuous for Inhibitors?
(1) Hanson SM et al. (2018). What Makes a Kinase Promiscuous for Inhibitors? Cell Chem Biol, S2451-9456(18)30412-4. doi: 10.1016/j.chembiol.2018.11.005. [Epub ahead of print]. [PMID:30612951]


Using the drug-protein interactome to identify anti-ageing compounds for humans
(1) Fuentealba M et al. (2019). Using the drug-protein interactome to identify anti-ageing compounds for humans. PLoS comput Biol, 15(1):e1006639. doi: 10.1371/journal.pcbi.1006639. [Epub ahead of print]. [PMID:30625143]


Chronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes
(1) Akilesh HM et al. (2019). Chronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes. Science, 363(6423). pii: eaao5213. doi: 10.1126/science.aao5213. [PMID:30630901]


New Cannabinoid Receptors Structures

Comments by Steve Alexander, IUPHAR/BPS Guide to PHARMACOLOGY, (@mqzspa)

Cannabinoid receptors respond to multiple endogenous fatty acid derivatives and are often divided into neuronal-associated CB1 receptors and immune cell-associated CB2 receptors. Both receptors are GPCR, coupled predominantly to Gi, and have cytoprotective properties. The predominant psychotropic agent in Cannabis, THC, acts as a partial agonist at both receptors. CB1 patho/physiological responses are often characterised as analgesic, rewarding, orexigenic, hypothermic and amnestic, while CB2 receptors are mostly associated with anti-inflammatory effects. Two Cell papers [1,2] describe new structures for these receptors. Read the full article on our blog

(1) Kumar K et al. (2018). Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. Cell, pii: S0092-8674(18)31565-4. doi: 10.1016/j.cell.2018.11.040. [Epub ahead of print]. [PMID:30639101]

(2) Liu X et al. (2018). Crystal Structure of the Human Cannabinoid Receptor CB2. Cell, pii: S0092-8674(18)31625-8. doi: 10.1016/j.cell.2018.12.011. [Epub ahead of print]. [PMID:30639103]


The IUPHAR Pharmacology Education Project
(1) Faccenda E et al. (2018). The IUPHAR Pharmacology Education Project. Clin Pharmacol Ther, 105(1):45-48. doi: 10.1002/cpt.1278. [PMID:30588614]


A patent review on PD-1/PD-L1 antagonists: small molecules, peptides, and macrocycles (2015-2018)
(1) Shaabani S et al. (2018). A patent review on PD-1/PD-L1 antagonists: small molecules, peptides, and macrocycles (2015-2018). Expert Opin Ther Pat, 28(9):665-678. doi: 10.1080/13543776.2018.1512706. [PMID:30107136]


BioTransformer: a comprehensive computational tool for small molecule metabolism prediction and metabolite identification
(1) Djoumbou-Feunang Y et al. (2019). BioTransformer: a comprehensive computational tool for small molecule metabolism prediction and metabolite identification. J Chemoinform, 11(1):2. doi: 10.1186/s13321-018-0324-5. [PMID:30612223]


GABAA receptor signalling mechanisms revealed by structural pharmacology
(1) Masiulis S et al. (2019). GABAA receptor signalling mechanisms revealed by structural pharmacology. Nat Commun., doi: 10.1038/s41586-018-0832-5. [Epub ahead of print]. [PMID:30602790]


Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists
(1) Schöppe J et al. (2019). Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists. Nat Commun., 10(1):17. doi: 10.1038/s41467-018-07939-8. [PMID:30604743]


The signposts and winding roads to immunity and inflammation
(1) Kanneganti TD (2019). The signposts and winding roads to immunity and inflammation. Nat Rev Immunol., doi: 10.1038/s41577-018-0108-1. [Epub ahead of print]. [PMID:30602731]


The Next Generation of Immunotherapy for Cancer: Small Molecules Could Make Big Waves
(1) Kerr WG & Chisholm JD (2019). The Next Generation of Immunotherapy for Cancer: Small Molecules Could Make Big Waves. J Immunol., 202(1):11-19. doi: 10.4049/jimmunol.1800991. [PMID:30587569]


The X-ray crystal structure of human endothelin 1, a polypeptide hormone regulator of blood pressure
(1) McPherson A & Larson SB (2019). The X-ray crystal structure of human endothelin 1, a polypeptide hormone regulator of blood pressure. Acta. Cryst., 75(Pt 1):47-53. doi: 10.1107/S2053230X18016011. [PMID:30605125]


December 2018

Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases
(1) Perry MWD et al. (2018). Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases. J Med Chem, doi: 10.1021/acs.jmedchem.8b01298. [Epub ahead of print]. [PMID:30582813]


GPR37/GPR37L1 and the putative pairing with prosaptide/PSAP

Dr. Nicola J. Smith, Victor Chang Cardiac Research Institute, Australia

As is often the case with orphan GPCRs, assigning the endogenous ligand has been controversial for the closely related peptide family orphans, GPR37 and GPR37L1. In 2013, Randy Hall and his team (PubMed: 23690594) first reported an association between both centrally-expressed orphan GPCRs and prosaposin (PSAP) and prosaptide (TX14A), the synthetic active epitope of PSAP. Since that time there has been much debate in the field about whether this pairing is correct, with some authors corroborating the findings (PubMed: 24371137; 30010619, 28795439) and others not (PubMed: 23396314; 27072655; 28688853). Note that Head Activator, found in Hydra, was earlier reported as a ligand (PubMed: 16443751) but was quickly discredited (PubMed:28688853; 23686350). A recent paper by Sergey Kasparov’s laboratory in Bristol has added further fuel to the fire. In a series of well controlled experiments, Liu et al. [1] provided convincing evidence that prosaptide is cyto- and neuro-protective and promotes chemotaxis. They are also the first group to demonstrate an effect of prosaptide at a more physiologically plausible potency. At the same time, Bang et al. [2] published a ground-breaking paper linking GPR37 expression to macrophage function. Moreover, they proposed a second, more potent ligand for GPR37 (GPR37L1 was not studied): the pro-resolving mediator neuroprotectin D1 (NPD1). Using HEK293 cells expressing GPR37, NPD1 was a potent stimulator of Gαi/o-dependent calcium flux; findings that were corroborated in macrophages isolated from wild type, but not GPR37 knock-out, mice (PubMed: 30010619). Thus, it may be that the endogenous ligand for GPR37 (and perhaps GPR37L1?) is not a peptide after all, but a lipid ... Read the full article on our blog

(1) Liu B et al. (2018). Glio- and neuro-protection by prosaposin is mediated by orphan G-protein coupled receptors GPR37L1 and GPR37. Glia, 66(11):2414-2426. doi: 10.1002/glia.23480. [PMID:30260505]

(2) Bang S et al. (2018). GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain. J Clin Invest, 128(8):3568-3582. doi: 10.1172/JCI99888. [PMID:30010619]


Improving the Gene Ontology Resource to Facilitate More Informative Analysis and Interpretation of Alzheimer's Disease Data
(1) Kramarz B et al. (2018). Improving the Gene Ontology Resource to Facilitate More Informative Analysis and Interpretation of Alzheimer's Disease Data. Genes (Basel), 9(12). pii: E593. doi: 10.3390/genes9120593. [PMID:30501127]


Structures shed light on prostanoid signaling
(1) Hollenstein K. (2018). Structures shed light on prostanoid signaling. Nat Chem Biol, 15(1):3-5. doi: 10.1038/s41589-018-0178-1. [PMID:30510191]


Systematic polypharmacology and drug repurposing via an integrated L1000-based Connectivity Map database mining
(1) Liu T-P et al. (2018). Systematic polypharmacology and drug repurposing via an integrated L1000-based Connectivity Map database mining. Royal Society Open Science, doi: https://doi.org/10.1098/rsos.181321. [Royal Society Open Science:Article]


QSAR-Based Virtual Screening: Advances and Applications in Drug Discovery
(1) Neves BJ et al. (2018).QSAR-Based Virtual Screening: Advances and Applications in Drug Discovery. Frontiers in Pharmacology, doi:https://doi.org/10.3389/fphar.2018.01275. [Frontiers:Mini Review Article]


Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
(1) Lombardo F et al. (2018). Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds. Drug Metab Dispos, 46(11):1466-1477. doi: 10.1124/dmd.118.082966. [PMID:30115648]


Web-Based Tools for Polypharmacology Prediction
(1) Awale M & Reymond JL (2018). Web-Based Tools for Polypharmacology Prediction. Methods Mol Biol, 1888:255-272. doi: 10.1007/978-1-4939-8891-4_15. [PMID:30519952]


Open-source discovery of chemical leads for next-generation chemoprotective antimalarials
(1) Antonova-Koch Y et al. (2018). Open-source discovery of chemical leads for next-generation chemoprotective antimalarials. Science, 362(6419). doi:10.1126/science.aat9446. [Science:Article]


The convergence of artificial intelligence and chemistry for improved drug discovery
(1) Wright SC et al. (2018). The convergence of artificial intelligence and chemistry for improved drug discovery. Future Med Chem, doi: 10.4155/fmc-2018-0161. [Epub ahead of print]. [PMID:30499699]


FZD5 is a Gαq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs
(1) Wright SC et al. (2018). FZD5 is a Gαq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs. Sci Signal, 11(559). pii: eaar5536. doi: 10.1126/scisignal.aar5536. [PMID:30514810]


Machine learning in chemoinformatics and drug discovery
(1) Lo CY et al. (2018). Machine learning in chemoinformatics and drug discovery. Drug Discov Today, 23(8):1538-1546. doi: 10.1016/j.drudis.2018.05.010. [PMID:29750902]


Structural basis for ligand recognition of the human thromboxane A2 receptor
(1) Fan H et al. (2018). Structural basis for ligand recognition of the human thromboxane A2 receptor. Nat Chem Biol, 15(1):27-33. doi: 10.1038/s41589-018-0170-9. [PMID:30510189]


Chemical space of naturally occurring compounds
(1) Saldivar-Gonzalez FI et al. (2018). Chemical space of naturally occurring compounds. Physical Sciences Reviews, doi: https://doi.org/10.1515/psr-2018-0103. [Link:Abstract]


Organic synthesis in a modular robotic system driven by a chemical programming language
(1) Steiner S et al. (2018). Organic synthesis in a modular robotic system driven by a chemical programming language. Science, pii: eaav2211. doi: 10.1126/science.aav2211. [Epub ahead of print]. [PMID:30498165]


The drug repurposing landscape from 2012 to 2017: evolution, challenges, and possible solutions
(1) Polamreddy P & Gattu N (2018). The drug repurposing landscape from 2012 to 2017: evolution, challenges, and possible solutions. Drug Discov Today, pii: S1359-6446(18)30282-4. doi: 10.1016/j.drudis.2018.11.022. [Epub ahead of print]. [PMID:30513339]


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:30449619]


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:30116974]


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:30405239]


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:30429472]


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:30362749]


Somatic APP gene recombination in normal and Alzheimer’s disease neurons

Comments by Jerold Chun, Sanford Burnham Prebys Medical Discovery Institute

A new facet of the human brain has been reported [1] involving a first example of somatic gene recombination in neurons, representing a normal neural mechanism whose disruption could underlie the most common (sporadic) forms of Alzheimer’s disease. Mosaic and somatic recombination of Amyloid Precursor Protein (APP) was identified in this well-known Alzheimer’s disease gene, where increased copies and mutations in rare families or Down syndrome are considered causal... Read the full article on our blog

(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:30464338]


Cellular thermal shift assays to measure ligand-to-target engagement

Comments by Dr. Thomas Lundbäck, Associate Director, Mechanistic Biology & Profiling, Discovery Sciences, AstraZeneca R&D, Gothenburg, Sweden

The cellular thermal shift assay (CETSA) was introduced in July of 2013 as a means to investigate drug target engagement inside live cells and tissues. The simplicity of CETSA has allowed prompt adoption in the literature but the importance of rapid changes in ligand binding is still not well recognised. To explore these considerations we systematically varied both the heat-pulse temperature and duration in CETSA using p38a as our model system [1]... Read the full article on our blog

(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:30418016]


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:30455414]


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:30442810]


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:30425369]


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:29202222]


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:30388399]


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:Abstract]


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:Abstract]


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:Abstract]


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:30405245]


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:30356040]


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:30359639]


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:28602761]


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:30371819]


October 2018

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


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:30356053]


Piezo channels and mechano-transduction in sensory neurons

Comments by Alistair Mathie (@AlistairMathie) and Emma L. Veale (@Ve11Emma), 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. Read the full article on our blog

(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: 30305457].

(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: 30361375].


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:Abstract]


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:30356220]


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:30078033]


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:30212196]


Role of RTP type D on reward association with cocaine administration

Comments by Steve Alexander, IUPHAR/BPS Guide to PHARMACOLOGY, (@mqzspa)

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. Read the full article on our blog

(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: 30348770]


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:30304474]


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:30346938]


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:30351302]


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:30190309]


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:30325568]


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]. [link to PDF]


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:30333485]


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:30323343]


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:30310233]


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:30310234]


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:30305759]


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:30305743]


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:30234987]


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:30266097]


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:29920198]


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:30144240]


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:29648583]


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:30269496]


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:30275042]


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:30285606]


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:30291362]


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:30282735]


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:30209399]


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:30220562]


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:30224653]


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:30113139]


Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor

Comments by Steve Alexander, IUPHAR/BPS Guide to PHARMACOLOGY, (@mqzspa)

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. Read the full article on our blog

(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: 30175587]


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:30175587]


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:30180973]


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:30140018]


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:30106578]


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:30101607]


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:30010333]


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:30140051]


β-Subunit of the voltage-gated Ca2+ channel Cav1.2 drives signaling to the nucleus via H-Ras

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. Read the full article on our blog

(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: 30150369]

(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: 11598293]

(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: 11226322]

(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: 30021858]


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:30135577]


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:30127358]


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:30127360]


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:30104700]


Challenges of Connecting Chemistry to Pharmacology: Perspectives from Curating the IUPHAR/BPS Guide to PHARMACOLOGY
(1) Southan C et al. (2018). Challenges of Connecting Chemistry to Pharmacology: Perspectives from Curating the IUPHAR/BPS Guide to PHARMACOLOGY. ACS Omega, 3(7):8408-8420. doi: 10.1021/acsomega.8b00884. [PMID:30087946]


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:30097821]


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:30035545]


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:30072576]


July 2018

Direct activation of neuronal KV7 channels by GABA and gabapentin – a novel mechanism for reducing neuronal excitability

Comments by Emma L. Veale (@Ve11Emma) and Alistair Mathie (@AlistairMathie)

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. Read the full article on our blog

(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: 29748663]

(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: 30021858]


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


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:30032202]


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:30033591]


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:29988083]


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:29877628]


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:29982784]


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:Abstract]


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:29949996]


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:29872227]


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:29398112]


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:29892073]


Archive of previous years