Hot topics in pharmacology

Recent publications of interest recommended by NC-IUPHAR

2019: Jan | Feb | Mar | Apr | May | Jun | Jul | Aug | Sep | Oct | Nov

November 2019

A New Alzheimer’s Approval in China
(1) Lowe D. (2019). In The Pipeline: A New Alzheimer’s Approval in China. Sci Trans Med, 10 May 2019. [In The Pipeline: Article]
(2) Wang X et al. (2019). Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer's disease progression. Cell Res., 29(10):787-803. doi: 10.1038/s41422-019-0216-x. [PMID: 31488882]


An Alzheimer's-disease-protective APOE mutation
(1) Zalocusky KA et al. (2019). An Alzheimer's-disease-protective APOE mutation. Nat Med, doi: 10.1038/s41591-019-0634-9. [PMID: 31686033]


Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of N-Methylation for PI3Kδ Activity
(1) Barnes L et al. (2019). Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of N-Methylation for PI3Kδ Activity. J Med Chem, doi: 10.1021/acs.jmedchem.9b01499. [PMID: 31647659]


An Alzheimer's-disease-protective APOE mutation
(1) Zalocusky KA et al. (2019). An Alzheimer's-disease-protective APOE mutation. Nat Med, doi: 10.1038/s41591-019-0634-9. [PMID: 31686033]


Discovery of ABBV/GLPG-3221, a Potent Corrector of CFTR for the Treatment of Cystic Fibrosis
(1) Scanio MJC et al. (2019). Discovery of ABBV/GLPG-3221, a Potent Corrector of CFTR for the Treatment of Cystic Fibrosis. ACS Med Chem Lett, doi: 10.1038/s41589-019-0387-2. [ACS: Letter]


Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptorsr
(1) Foster S et al. (2019). Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors. Cell, doi: 10.1016/j.cell.2019.10.010. [Cell: Full text]


October 2019

Structure of an allosteric modulator bound to the CB1 cannabinoid receptor
(1) Shao Z et al. (2019). Structure of an allosteric modulator bound to the CB1 cannabinoid receptor. Nat Chem Biol, doi: 10.1038/s41589-019-0387-2. [PMID: 31659318]


Structural basis of species-selective antagonist binding to the succinate receptor
(1) Haffke M et al. (2019). Structural basis of species-selective antagonist binding to the succinate receptor. Nature, 574(7779):581-585. doi: 10.1038/s41586-019-1663-8. [PMID: 31645725]


A Point of Inflection and Reflection on Systems Chemical Biology
(1) Johnson EO & Hung DT. (2019). A Point of Inflection and Reflection on Systems Chemical Biology. ACS Chem Biol, doi: 10.1021/acschembio.9b00714. [PMID: 31613592]


From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9
(1) Petrilli WL et al. (2019). From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9. Cell Chem Biol, pii: S2451-9456(19)30322-8. doi: 10.1016/j.chembiol.2019.10.002. [PMID: 31653597]


A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor
(1) Dekan Z et al. (2019). A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor. Proc Natl Acad Sci USA, 116(44):22353-22358. doi: 10.1073/pnas.1908662116. [PMID: 31611414]


Hot Topics: 3D structure of the full-length P2X7 receptor provides insight into factors controlling agonist potency and receptor desensitisation

Comments by Charles Kennedy, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde

P2X receptors are ligand-gated cation channels for which ATP is the endogenous orthosteric agonist. Seven P2X subunits have been identified and they form trimers to produce at least twelve different receptor subtypes. The tertiary structure of several subtypes have been reported, but they all lack clear information on the conformation of the N- and C-terminal cytoplasmic domains because of the truncated constructs used and the flexibility of these domains. Now, McCarthy et al., (1) report single-particle cryo-EM images of the full-length rat P2X7 receptor in both apo (closed pore) and ATP-bound (open pore) states, which suggest why the affinity of this receptor for ATP is low, indicate how cysteine residues in the C-terminal control desensitisation and reveal a surprising guanine nucleotide binding site in the C-terminal. Read the full article on our blog

(1) McCarthy et al. (2019). Full-length P2X7 structures reveal how palmitoylation prevents channel desensitization. Cell. https://doi.org/10.1016/j.cell.2019.09.017. [ScienceDirect: View Article]


September 2019

A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity
(1) Tran KT et al. (2019). A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity. J Med Chem, 62(17):8028-8052. doi: 10.1021/acs.jmedchem.9b00723. [PMID: 31411465]


Advances and Challenges in Rational Drug Design for SLCs
(1) Garibsingh RA & Schlessinger A et al. (2019). Advances and Challenges in Rational Drug Design for SLCs. Trends Pharmacol Sci, doi.org/10.1016/j.immuni.2019.08.008. [PMID: 31519459]


Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database
(1) Nguengang Wakap S et al. (2019). Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet, doi: 10.1038/s41431-019-0508-0. [PMID: 31527858]


August 2019

Single-Cell Analysis of Human Mononuclear Phagocytes Reveals Subset-Defining Markers and Identifies Circulating Inflammatory Dendritic Cells
(1) Dutertre C-A et al. (2019). Single-Cell Analysis of Human Mononuclear Phagocytes Reveals Subset-Defining Markers and Identifies Circulating Inflammatory Dendritic Cells. Immunity, doi.org/10.1016/j.immuni.2019.08.008. [Immunity: View Article]


A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity
(1) Tran KT et al. (2019). A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity. J Med Chem, doi: 10.1021/acs.jmedchem.9b00723. [PMID: 31411465]


SEP-363856, A NOVEL PSYCHOTROPIC AGENT WITH A UNIQUE, NON-D2 RECEPTOR MECHANISM OF ACTION
(1) Dedic N et al. (2019). SEP-363856, A NOVEL PSYCHOTROPIC AGENT WITH A UNIQUE, NON-D2 RECEPTOR MECHANISM OF ACTION. J Pharmacol Exp Ther, pii: jpet.119.260281. doi: 10.1124/jpet.119.260281. [PMID: 31371483]


Hot Topics: GPR139 as a potential target for increasing opioid safety

Comments by Simon R. Foster, Monash University and Professor David E. Gloriam, University of Copenhagen and Head of GPCRdb (@David_Gloriam)

The cross-talk between different G protein-coupled receptor signal-transduction pathways is an intriguing concept with important physiological implications [1]. A recent study by Wang et al. [2] has discovered that the actions of opioid drugs on the μ-opioid receptor (MOR) are negatively regulated by an interaction with the undercharacterized GPR139 receptor [3]. These findings implicate GPR139 as a potential target for increasing opioid safety. Read the full article on our blog

(1) Selbie, L. A. & Hill, S. J. G protein-coupled-receptor cross-talk: the fine-tuning of multiple receptor-signalling pathways. Trends in pharmacological sciences 19, 87-93, (1998). [PMID: 9584624]

(2) Wang, D. et al. Genetic behavioral screen identifies an orphan anti-opioid system. Science (New York, N.Y.), eaau2078, (2019). [PMID: 31416932]

(3) Vedel, L., Nohr, A. C., Gloriam, D. E. & Brauner-Osborne, H. Pharmacology and function of the orphan GPR139 G protein-coupled receptor. Basic & clinical pharmacology & toxicology, (2019). [PMID: 31132229]


Over 1,000 genetic loci influencing blood pressure with multiple systems and tissues implicated
(1) Cabrera CP et al. (2019). Over 1,000 genetic loci influencing blood pressure with multiple systems and tissues implicated. Hum Mol Genet, pii: ddz197. doi: 10.1093/hmg/ddz197. [PMID: 31411675]


Large-Scale Analyses of Human Microbiomes Reveal Thousands of Small, Novel Genes
(1) Sberro H et al. (2019). Large-Scale Analyses of Human Microbiomes Reveal Thousands of Small, Novel Genes. Cell, pii: S0092-8674(19)30781-0. doi: 10.1016/j.cell.2019.07.016. [PMID: 31402174]


Resting-State Structure and Gating Mechanism of a Voltage-Gated Sodium Channel

Comments by Jörg Striessnig, University of Innsbruck

In this report the Catterall laboratory succeeded in solving the high resolution structure of a voltage-gated Na+-channel (Nav) in its resting state (1). Why is this difficult and why is this important? It is difficult because Navs exist in the resting state only at very negative voltages but not at a zero membrane potential required for structural analysis by X-ray crystallography or cryo-EM. Accordingly, all high resolution structures of Navs, whether pro- or eukaryotic, have so far reported channels with the voltage-sensing domains in the depolarized state, i.e. the positively charges S4 helices of the voltage sensors moved "up" towards the extracellular side. Therefore it is not known how the activation gate of the ion pore (formed by the four S6 helices) is kept closed by the voltage sensor in its resting position, i.e. with the S4-helices "down". Read the full article on our blog

(1) Wisedchaisri G et al. (2019). Resting-State Structure and Gating Mechanism of a Voltage-Gated Sodium Channel. Cell, 178(4):993-1003.e12. doi: 10.1016/j.cell.2019.06.031. [PMID: 31353218]


Identification of a novel allosteric GLP–1R antagonist HTL26119 using structure- based drug design
(1) O'Brien A et al. (2019). Identification of a novel allosteric GLP–1R antagonist HTL26119 using structure- based drug design. Biol Med Chem Lett, doi: 10.1016/j.bmcl.2019.08.015. [ScienceDirect: Abstract]


Visualization of drug target interactions in the contexts of pathways and networks with ReactomeFIViz
(1) Blucher AS et al. (2019). Visualization of drug target interactions in the contexts of pathways and networks with ReactomeFIViz. F1000 Res, doi: 10.12688/f1000research.19592.1. [PMID: 31372215]


Structure and mechanism of the cation-chloride cotransporter NKCC1
(1) Chew TA et al. (2019). Structure and mechanism of the cation-chloride cotransporter NKCC1. Nature, doi: 10.1038/s41586-019-1438-2. [PMID: 31367042]


Building a Hybrid Physical-Statistical Classifier for Predicting the Effect of Variants Related to Protein-Drug Interactions
(1) Wang B et al. (2019). Building a Hybrid Physical-Statistical Classifier for Predicting the Effect of Variants Related to Protein-Drug Interactions. Structure, pii: S0969-2126(19)30200-X. doi: 10.1016/j.str.2019.06.001. [PMID: 31279629]


Revisiting the classification of adhesion GPCRs
(1) Scholz N et al. (2019). Revisiting the classification of adhesion GPCRs. Ann N Y Acad Sci, doi: 10.1111/nyas.14192. [PMID: 31365134]


July 2019

The atlas of aminergic GPCR mutagenesis

Comments by Chris De Graaf (@Chris_de_Graaf)

G protein-coupled receptors (GPCRs) are an important family of signal-transducing membrane proteins capable of binding various types of ligands from the extracellular space and activating various signalling pathways inside the cell, rendering them one of the largest protein target families in pharmaceutical research [1]. Receptors of the aminergic GPCRs family are particularly rewarding drug targets as they are implicated in various disease areas, and structure-based drug design has enabled the understanding of ligand binding and function, and the development of more than 500 approved drugs targeting these receptors. Advances in structural biology allowed the determination of more than 300 crystal structures of more than 60 GPCR subtypes to date [2], however, these still represent only a small fraction of known receptor-ligand associations [3]. Site-directed mutagenesis (SDM) is a versatile and frequently employed tool in pharmacological investigations used to infer structural features of protein-ligand interactions [4]. Mutation studies complement structural information provided by crystal structures by defining the roles and relative importance of residues involved in binding, functional activity, and selectivity for ligand chemotypes which have not yet been co-crystallized with their receptors. Community-wide GPCR structure modelling challenges have shown that the best models could be constructed by careful incorporation of mutation and SAR data relating to ligand binding [5]. However, an integrated analysis of receptor and ligand structures and SAR, mutation data, and binding mode prediction has been so far lacking. The study of Vass et al. can be regarded as a meta-analysis of the site-directed mutagenesis literature for aminergic G protein-coupled receptors [6]. Read the full article on our blog

(1) Santos et al. (2017). A comprehensive map of molecular drug targets. Nat Rev Drug Discov. doi: 10.1038/nrd.2016.230. [PMIDs: 27910877]

(2) Munk et al. (2019). An online resource for GPCR structure determination and analysis. Nat Methods. doi: 10.1038/s41592-018-0302-x. [PMIDs: 30664776]

(3) Vass et al. (2018). Chemical Diversity in the G Protein-Coupled Receptor Superfamily. Trends Pharmacol Sci. doi: 10.1016/j.tips.2018.02.004. [PMIDs: 29576399]

(4) a) Munk et al. (2016). Integrating structural and mutagenesis data to elucidate GPCR ligand binding. Curr Opin Pharmacol. doi: 10.1016/j.coph.2016.07.003. [PMIDs: 27475047] b) Arimont et al. (2017) Structural Analysis of Chemokine Receptor–Ligand Interactions. J Med Chem doi: 10.1021/acs.jmedchem.6b0130. [PMIDs: 28165741]. c) Jespers et al. (2018). Structural Mapping of Adenosine Receptor Mutations: Ligand Binding and Signaling Mechanisms. Trends Pharmacol Sci. doi: 10.1016/j.tips.2017.11.001. [PMIDs: 29203139]

(5) a) Kufareva et al. (2011) Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment. Structure. doi: 10.1016/j.str.2011.05.012. [PMIDs: 21827947]; b) Kufareva et al. (2014). Advances in GPCR modeling evaluated by the GPCR Dock 2013 assessment: meeting new challenges. Structure. doi: 10.1016/j.str.2014.06.012. [PMIDs: 25066135]

(6) Vass et al. (2019). Aminergic GPCR-Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data. J Med Chem. doi: 10.1021/acs.jmedchem.8b00836. [PMIDs: 30351004]


EPA’s DSSTox Database: History of development of a curated chemistry resource supporting computational toxicology research
(1) Grulke CM et al. (2019). EPA’s DSSTox Database: History of development of a curated chemistry resource supporting computational toxicology research. computational Toxicology, https://doi.org/10.1016/j.comtox.2019.100096. [ScienceDirect: Abstract]


Sharing of clinical trial data and results reporting practices among large pharmaceutical companies: cross sectional descriptive study and pilot of a tool to improve company practices
(1) Miller J et al. (2019). Sharing of clinical trial data and results reporting practices among large pharmaceutical companies: cross sectional descriptive study and pilot of a tool to improve company practices. BMJ, 366:l4217. doi: 10.1136/bmj.l4217. [PMID: 31292127]


New drugs: where did we go wrong and what can we do better?
(1) Wieseler B et al. (2019). New drugs: where did we go wrong and what can we do better?. BMJ, 366:l4340. doi: 10.1136/bmj.l4340. [PMID: 31292109]


A genetics-led approach defines the drug target landscape of 30 immune-related traits
(1) Fang H et al. (2019). A genetics-led approach defines the drug target landscape of 30 immune-related traits. Nat Genet, 51(7):1082-1091. doi: 10.1038/s41588-019-0456-1. [PMID: 31253980]


The human endogenous metabolome as a pharmacology baseline for drug discovery
(1) Bofill et al. (2019). The human endogenous metabolome as a pharmacology baseline for drug discovery. Drug Discov Today, pii: S1359-6446(19)30104-7. doi: 10.1016/j.drudis.2019.06.007. [PMID: 31226432]


Chemokine receptor crystal structures: what can be learnt from them?
(1) Arimont M et al. (2019). Chemokine receptor crystal structures: what can be learnt from them?. Mol Pharmacol, pii: mol.119.117168. doi: 10.1124/mol.119.117168. [PMID: 31266800]


June 2019

Predicting and Understanding the Human Microbiome's Impact on Pharmacology
(1) Hitchings R & Kelly L. (2019). Predicting and Understanding the Human Microbiome's Impact on Pharmacology. Trends Pharmacol Sci,pii: S0165-6147(19)30091-4. doi: 10.1016/j.tips.2019.04.014. [PMID: 31171383]


The Complement Receptor C5aR2: A Powerful Modulator of Innate and Adaptive Immunity
(1) Li XX et al. (2019). The Complement Receptor C5aR2: A Powerful Modulator of Innate and Adaptive Immunity. J Immunol, 202(12):3339-3348. doi: 10.4049/jimmunol.1900371. [PMID: 31160390]


Understanding ligand binding selectivity in a prototypical GPCR family
(1) Mattedi G et al. (2019). Understanding ligand binding selectivity in a prototypical GPCR family. J Chem Inf Model, doi: 10.1021/acs.jcim.9b00298. [PMID: 31125224]


Functional characterization of 3D protein structures informed by human genetic diversity
(1) Hicks M et al. (2019). Functional characterization of 3D protein structures informed by human genetic diversity. PNAS USA, 116(18):8960-8965. doi: 10.1073/pnas.1820813116. [PMID: 30988206]


Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi
(1) Qi X et al. (2019). Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi. Nature, doi: 10.1038/s41586-019-1286-0. [PMID: 31168089]


PRECOG: PREdicting COupling probabilities of G-protein coupled receptors
(1) Singh G et al. (2019). PRECOG: PREdicting COupling probabilities of G-protein coupled receptors. Nucleic Acids Res, pii: gkz392. doi: 10.1093/nar/gkz392. [PMID: 31143927]


Capturing mixture composition: an open machine-readable format for representing mixed substances
(1) Clark AM et al. (2019). Capturing mixture composition: an open machine-readable format for representing mixed substances. J Cheminform, 11(1):33. doi: 10.1186/s13321-019-0357-4. [PMID: 31124006]


Drug-Target Association Kinetics in Drug Discovery
(1) IJzermann AP & Guo D (2019). Drug-Target Association Kinetics in Drug Discovery. Trends Biochem Sci, S0968-0004(19)30084-2. doi: 10.1016/j.tibs.2019.04.004. [PMID: 31101454]


May 2019

Depressive disorders: Treatment failures and poor prognosis over the last 50 years
(1) Warne T et al. (2019). Depressive disorders: Treatment failures and poor prognosis over the last 50 years. Pharmacol Res Perspect, 7(3):e00472. doi: 10.1002/prp2.472. [PMID: 31072904]


No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples
(1) Border R et al. (2019). No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples. Am J Psychiatry, 176(5):376-387. doi: 10.1176/appi.ajp.2018.18070881. [PMID: 30845820]


There is no "Depression Gene"
(1) Lowe D. (2019). In The Pipeline: There is no "Depression Gene". Sci Trans Med, 10 May 2019. [In The Pipeline: Article]


Time to FRET about GPCR activation dynamics?

Comments by Shane D Hellyer and Karen J Gregory, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Australia

G protein coupled receptors (GPCRs) are crucial for the transduction of extracellular stimuli to the intracellular space. Upon activation, GPCRs undergo large conformational changes to engage transducers and stimulate intracellular responses. However, the kinetics of agonist induced GPCR conformational changes are relatively understudied. An exception to this is the class A rhodopsin receptor, which has a covalent agonist and fast (< 1ms) activation kinetics. In contrast, other GPCRs are thought to activate across the low to mid millisecond range [1]. For Class C GPCRs, which are distinct from class A receptors in that they contain large extracellular agonist binding domains and exist as obligate dimers, the site of agonist binding is >100Å from where the transducer interacts [2]. Class C GPCR activation involves both dimer rearrangement and activation of the 7-transmembrane (7-TM) domain, which are thought to occur over 20-200ms [3-5]. An outstanding question is whether the activation kinetics of rhodopsin are indeed faster than other GPCRs, or if previous experimental approaches lacked sufficient resolution to reveal fast kinetics in other receptor families. To this end, Grushevskyi and colleagues have used FRET recordings to detect submillisecond activation dynamics of a prototypical class C GPCR, metabotropic glutamate receptor subtype 1 (mGlu1), demonstrating that mGlu1 undergoes two temporally distinct conformational changes upon activation [6]. Read the full article on our blog

(1) Lohse M.J. et al. (2012). Fluorescence/bioluminescence resonance energy transfer techniques to study G protein-coupled receptor activation and signalling. Pharmacol Rev, 64: 299-336. [PMIDs: 22407612]

(2) Leach K & Gregory K.J. (2017) Molecular insights into allosteric modulation of Class C G protein-coupled receptors. Pharmacol Res, 116: 105-118. [PMIDs: 27965032]

(3) Hlacvackova V et al. (2012) Sequential inter- and intrasubunit rearrangements during activation of dimeric metabotropic glutamate receptor 1. Sci Signal, 5: ra59. [PMIDs: 22894836]

(4) Marcaggi P et al. (2009) Optical measurement of mGluR1 conformational changes reveals fast activation, slow deactivation, and sensitization. PNAS, 106: 11388-11393. [PMIDs: 19549872]

(5) Vafabakhsh R et al. (2015) Conformational dynamics of a class C G-protein-coupled receptor. Nature, 524: 497-501. [PMIDs: 26258295]

(6) Grushevskyi E.O. et al. (2019) Stepwise activation of a class C GPCR begins with millisecond dimer rearrangement. PNAS. pii: 201900261. doi:10.1073/pnas.1900261116. [Epub ahead of print] [PMIDs: 31023886]


Molecular basis for high-affinity agonist binding in GPCRs
(1) Warne T et al. (2019). Molecular basis for high-affinity agonist binding in GPCRs. Science, pii: eaau5595. doi: 10.1126/science.aau5595. [PMID: 31072904]


Aminergic GPCR-Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data
(1) Vass M et al. (2019). Aminergic GPCR-Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data. J Med Chem, 62(8):3784-3839. doi: 10.1021/acs.jmedchem.8b00836. [PMID: 30351004]


Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine
(1) Yñigez-Guitierrez AR & Bachmann BO (2019). Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine. J Med Chem, doi: 10.1021/acs.jmedchem.9b00246. [PMID: 31026161]


April 2019

Structural basis of ligand recognition at the human MT1 melatonin receptor
(1) Stauch B et al. (2019). Structural basis of ligand recognition at the human MT1 melatonin receptor. Nature, https://doi.org/10.1038/s41586-019-1141-3. [Nature: Article]


XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity
(1) Johansson LC et al. (2019). XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity. Nature, https://doi.org/10.1038/s41586-019-1144-0. [Nature: Article]


Analysis of tractable allosteric sites in G protein-coupled receptors
(1) Wakefield AE et al. (2019). Analysis of tractable allosteric sites in G protein-coupled receptors. Sci Rep, 9(1):6180. doi: 10.1038/s41598-019-42618-8. [PMID:30992500]


Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug-Target Interactions
(1) Lu S & Zhang J. (2019). Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug-Target Interactions. J Med Chem, 62(1):24-45. doi: 10.1021/acs.jmedchem.7b01844. [PMID:29457894]


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]


Functional characterization of 3D protein structures informed by human genetic diversity
(1) Hicks M et al. (2019). Functional characterization of 3D protein structures informed by human genetic diversity. PNAS USA, pii: 201820813. doi: 10.1073/pnas.1820813116. [Epub ahead of print]. [PMID:30988206]


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]


Archive of previous years