Hot Topics in Pharmacology

Coronavrius Information

We are currently collating information related to SARS-CoV-2 and COVID-19 at a dedicated coronavirus information page. This contains details of ligands and targets relevant to COVID-19 and links to useful resources and publications.

Recent publications of interest recommended by NC-IUPHAR

2020: Jul | Jun | May | Mar | Feb | Jan
2019: Dec | Nov | Oct | Sep | Aug

    July 2020


  • Structural basis of CXC chemokine receptor 2 activation and signalling.
    Liu K, Wu L, Yuan S, Wu M, Xu Y, Sun Q, Li S, Zhao S, Hua T, Liu ZJ. Structural basis of CXC chemokine receptor 2 activation and signalling. (2020)  Nature, [Epub ahead of print]. [PMID:32610344]

  • Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor.
    Mafi A, Kim SK, Goddard 3rd WA. Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor. (2020)  Proc. Natl. Acad. Sci. U.S.A., [Epub ahead of print]. [PMID:32601232]

  • June 2020


  • The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides.
    Meyrath M, Szpakowska M, Zeiner J, Massotte L, Merz MP, Benkel T, Simon K, Ohnmacht J, Turner JD, Krüger R et al.. The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides. (2020)  Nat Commun, 11 (1): 3033. [PMID:32561830]

  • Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice.
    Mock ED, Mustafa M, Gunduz-Cinar O, Cinar R, Petrie GN, Kantae V, Di X, Ogasawara D, Varga ZV, Paloczi J et al.. Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice. (2020)  Nat. Chem. Biol., 16 (6): 667-675. [PMID:32393901]

  • Hot Topics: TMEM163 Regulates ATP-Gated P2X Receptor and Behavior.

    Comments by Charles Kennedy, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK. Chair for NC-IUPHAR Subcommitee for P2X receptors.

    It is now clear that ligand-gated ion channels (LGICs) are not "stand alone" functional units, but form complexes with other components, including scaffolding proteins, regulatory proteins and enzymes. Besides their important physiological roles, these modulating proteins are also potential targets for drug discovery. P2X receptors are LGICs for which ATP is the endogenous agonist. Seven P2X subunits have been identified and they form trimers to produce at least twelve different receptor subtypes. Here, the authors combined a genome-wide open reading frame (ORF) collection with high-throughput functional screening, to search for P2X receptor modulators [54].. Read the full article on our blog

  • Discovery of polypeptide ligand-receptor pairs based on their co-evolution.
    Hsueh AJW, Feng Y. Discovery of polypeptide ligand-receptor pairs based on their co-evolution. (2020)  FASEB J., [Epub ahead of print]. [PMID:32501617]

  • Agonist binding directs dynamic competition among nuclear receptors for heterodimerization with retinoid X receptor.
    Fadel L, Rehó B, Volkó J, Bojcsuk D, Kolostyák Z, Nagy G, Müller G, Simándi Z, Hegedüs É, Szabó G et al.. Agonist binding directs dynamic competition among nuclear receptors for heterodimerization with retinoid X receptor. (2020)  J. Biol. Chem., [Epub ahead of print]. [PMID:32513869]

  • Fentanyl but not Morphine Interacts with Non-Opioid Recombinant Human Neurotransmitter Receptors and Transporters.
    Torralva R, Eshleman AJ, Swanson TL, Schmachtenberg JL, Schutzer WE, Bloom SH, Wolfrum KM, Reed JF, Janowsky A. Fentanyl but not Morphine Interacts with Non-Opioid Recombinant Human Neurotransmitter Receptors and Transporters. (2020)  J. Pharmacol. Exp. Ther., [Epub ahead of print]. [PMID:32513839]

  • Cryo-EM structures of inactive and active GABAB receptor.
    Mao C, Shen C, Li C, Shen DD, Xu C, Zhang S, Zhou R, Shen Q, Chen LN, Jiang Z et al.. Cryo-EM structures of inactive and active GABAB receptor. (2020)  Cell Res., [Epub ahead of print]. [PMID:32494023]

  • Does In Vitro Potency Predict Clinically Efficacious Concentrations?.
    Jansson-Löfmark R, Hjorth S, Gabrielsson J. Does In Vitro Potency Predict Clinically Efficacious Concentrations?. (2020)  Clin. Pharmacol. Ther., [Epub ahead of print]. [PMID:32275768]

  • Evaluating drug targets through human loss-of-function genetic variation.
    Minikel EV, Karczewski KJ, Martin HC, Cummings BB, Whiffin N, Rhodes D, Alföldi J, Trembath RC, van Heel DA, Daly MJ et al.. Evaluating drug targets through human loss-of-function genetic variation. (2020)  Nature, 581 (7809): 459-464. [PMID:32461653]

  • May 2020


  • Hot Topics: A trio of GPCR peptide publications

    Comments by Chris Southan, Fellow of the University Edinburgh, Owner of TW2Informatics , Chair of NC-IUPHAR Subcommitees for Proteases and Drug Targets and Chemistry (DRUTACS).

    This post covers three recent publications with a common theme and whose authors are collaborators with GtoPdb, thus making them as a trio particularly suitable for combined review. These are; Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors [22], Novel approaches leading towards peptide GPCR de-orphanisation [27], and Advances in therapeutic peptides targeting G protein-coupled receptors (see Davenport et al., 2020). As expected, these are all clearly written, contain valuable detail and each includes its own introduction. Therefore this piece does not need to go over these works per se but simply point out their coverage, domain of application, along with brief explanations of entity linking and/or external look-up options.. Read the full article on our blog

  • 15 drugs being tested to treat COVID-19 and how they would work.
    Shaffer L. 15 drugs being tested to treat COVID-19 and how they would work. (2020)  Nat. Med., [Epub ahead of print]. [PMID:32415251]

  • Structure of replicating SARS-CoV-2 polymerase.
    Hillen HS, Kokic G, Farnung L, Dienemann C, Tegunov D, Cramer P. Structure of replicating SARS-CoV-2 polymerase. (2020)  Nature, [Epub ahead of print]. [PMID:32438371]

  • Construction of a human cell landscape at single-cell level.
    Han X, Zhou Z, Fei L, Sun H, Wang R, Chen Y, Chen H, Wang J, Tang H, Ge W et al.. Construction of a human cell landscape at single-cell level. (2020)  Nature, 581 (7808): 303-309. [PMID:32214235]

  • Connecting data, tools and people across Europe: ELIXIR's response to the COVID-19 pandemic.
    Blomberg N, Lauer KB. Connecting data, tools and people across Europe: ELIXIR's response to the COVID-19 pandemic. (2020)  Eur. J. Hum. Genet., 28 (6): 719-723. [PMID:32415272]

  • Novel approaches and current challenges with targeting the endocannabinoid system.
    Morales P, Jagerovic N. Novel approaches and current challenges with targeting the endocannabinoid system. (2020)  Expert Opin Drug Discov,: 1-14 [Epub ahead of print]. [PMID:32336154]

  • March 2020


  • Who Bears the Burden of Long-Lived Molecular Biology Databases?.
    Imker HJ. Who Bears the Burden of Long-Lived Molecular Biology Databases?. (2020)  bioRxiv,. DOI: https://doi.org/10.1101/552067

  • The ELIXIR Core Data Resources: fundamental infrastructure for the life sciences.
    Drysdale R, Cook CE, Petryszak R, Baillie-Gerritsen V, Barlow M, Gasteiger E, Gruhl F, Haas J, Lanfear J, Lopez R et al.. The ELIXIR Core Data Resources: fundamental infrastructure for the life sciences. (2020)  Bioinformatics, 36 (8): 2636-2642. [PMID:31950984]

  • February 2020


  • Hot Topics: Cardiac Ca2+ Channel Regulation in the Fight-or-Flight Response: the monomeric small G-protein as another piece in the puzzle

    Comments by Jörg Striessnig, University of Innsbruck, Chair for NC-IUPHAR Subcommitee for Voltage-gated calcium channels, Liaison for NC-IUPHAR subcommittees on Voltage-gated ion channels

    Thirty eight years after the discovery that injection of the catalytic subunits of cyclic AMP-dependent protein kinase A (PKA) into isolated pig ventricular cardiac myocytes increases the amplitude of L-type Ca2+ current (today known to be formed by Cav1.2 channels), we are now getting close to understand the responsible molecular mechanism. Using an elegant transgenic approach Liu et al. (2020) [37] show that expression of channel complexes with all PKA consensus sites mutated to alanine in the Cav1.2 α1 and the β2 subunits has no effects on β-adrenergic modulation. Assuming that other proteins may be involved in this regulatory pathway, Liu et al. used a biotinylation-based proteomic proximity assay to identify proteins in the Cav1.2 neighborhood regulated by isoproterenol treatment in cardiomyocytes. This led to the discovery of the small Ras-like G protein Rad as a potential candidate. It belongs to the family of the Rad, Rem, Rem2 and Gem/Kir (RGK) Ras-like GTP-binding proteins, which were shown earlier to inhibit high-voltage-activated Ca2+ channels by binding to their β-subunits. Indeed, Rad appears to be the long-sought missing piece in the puzzle: in HEK293T Rad-mediated inhibition of cardiac Cav1.2 channels was relieved by PKA phosphorylation. Read the full article on our blog

  • Hot Topics: Virtual screening on the crystal structure of the G protein-coupled melatonin MT1 receptor reveals several new chemical scaffolds with biological activity

    Comments by Ralf Jockers, Institut Cochin, CNRS, INSERM, Université de Paris, Paris, France, Chair for NC-IUPHAR Subcommitee for Melatonin receptors.

    Melatonin targets two high-affinity receptors, MT1 and MT2, that belong to the G protein-coupled receptor (GPCR) superfamily. Drugs acting on melatonin receptors are subscribed for circadian disorders (jet lag, shift work, etc.), insomnia and major depression. All marketed drugs are non-selective agonists targeting both receptor types so far. Despite large chemical synthesis campaigns over the last 20 years, the pharmacology of melatonin receptors remains poorly explored with few inverse agonistic and signaling pathway-biased compounds and few selective compounds, in particular for the MT1 type. This lack of pharmacological tools goes along with a rather poor diversity in terms of chemical scaffolds currently available. Put into this context, a virtual screening looked like a very promising approach to increase the diversity of chemical scaffolds for melatonin receptors, especially now that the crystal structure of the MT1 receptor has been solved. The outcome of the virtual screening study performed by Stein et al. met these high expectations. Overall, 15 new chemical scaffolds were identified from the primary docking of over 150 million virtual molecules. Some of the primary hits had pEC50 values around 1nM, which is remarkable.. Read the full article on our blog

  • Hot Topics: Cannabinoid receptor structures

    Comments by Prof. Steve Alexander (@mqzspa), University of Nottingham, UK

    Two new reports cover further aspects of cannabinoid receptor binding as defined using cryo-EM. These expand on previous reports of the structure of the human CB1 cannabinoid receptor with the antagonists taranabant and AM6538 bound, and with the agonists MDMB-Fubinaca, AM11542 and AM841 bound. Previously reported also is the structure of the CB2 cannabinoid receptor with the antagonist AM10257 bound.. Read the full article on our blog

  • Hot Topics: A brief update on coronaviruses

    Prof. Michael Spedding, Spedding Reseach Solutions; Prof. Steve Alexander (@mqzspa), University of Nottingham; Dr. Elena Faccenda, University of Edinburgh; and Prof. Francesca Levi-Schaffer, The Hebrew University of Jerusalem.

    The new respiratory coronavirus from Wuhan in China is causing intense research activity in the world. Viruses are evidently associated with respiratory infections ranging in severity from the common cold to pneumonia and death. More than 200 viral types have been associated with the common cold, of which 50% of infections are rhinovirus, but also respiratory syncitial virus, influenza - and coronaviruses, particularly human coronavirus-229E (HCoV-229E), which is 'relatively benign'. Monocytes are relatively resistant to HcoV-229E infection, but rapidly invades, replicates in, and kills dendritic cells within a few hours of infection. Dendritic cells are the sentinel cells in the respiratory tract, and plasmacytoid dendritic cells are a crucial antiviral defence via interferon production. Thus, these viruses can impair control of viral dissemination and the formation of long-lasting immune memory. Read the full article on our blog

  • January 2020


  • Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10-2474.
    Bonifácio MJ, Sousa F, Aires C, Loureiro AI, Fernandes-Lopes C, Pires NM, Palma PN, Moser P, Soares-da-Silva P. Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10-2474. (2020)  Br. J. Pharmacol., 177 (9): 2123-2142. [PMID:31901141]

  • Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics.
    Ast J, Arvaniti A, Fine NHF, Nasteska D, Ashford FB, Stamataki Z, Koszegi Z, Bacon A, Jones BJ, Lucey MA et al.. Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics. (2020)  Nat Commun, 11 (1): 467. [PMID:31980626]

  • Quantitative Proteomics of the Cancer Cell Line Encyclopedia.
    Nusinow DP, Szpyt J, Ghandi M, Rose CM, McDonald 3rd ER, Kalocsay M, Jané-Valbuena J, Gelfand E, Schweppe DK, Jedrychowski M et al.. Quantitative Proteomics of the Cancer Cell Line Encyclopedia. (2020)  Cell, 180 (2): 387-402.e16. [PMID:31978347]

  • Structural insight into small molecule action on Frizzleds.
    Kozielewicz P, Turku A, Bowin CF, Petersen J, Valnohova J, Cañizal MCA, Ono Y, Inoue A, Hoffmann C, Schulte G. Structural insight into small molecule action on Frizzleds. (2020)  Nat Commun, 11 (1): 414. [PMID:31964872]

  • Identifying drug targets in tissues and whole blood with thermal-shift profiling.
    Perrin J, Werner T, Kurzawa N, Rutkowska A, Childs DD, Kalxdorf M, Poeckel D, Stonehouse E, Strohmer K, Heller B et al.. Identifying drug targets in tissues and whole blood with thermal-shift profiling. (2020)  Nat. Biotechnol., 38 (3): 303-308. [PMID:31959954]

  • Rigor and Transparency Index, a new metric of quality for assessing biological and medical science methods.
    Menke J, Roelandse M, Ozyurt B, Martone M, Bandowski A. Rigor and Transparency Index, a new metric of quality for assessing biological and medical science methods. (2020)  bioRxiv, preprint. DOI: 10.1101/2020.01.15.908111v1

  • Combined Computational and Structural Approach into Understanding the Role of Peptide Binding and Activation of Melanocortin Receptor 4.
    Zachmann J, Kritsi E, Tapeinou A, Zoumpoulakis P, Tselios T, Matsoukas MT. Combined Computational and Structural Approach into Understanding the Role of Peptide Binding and Activation of Melanocortin Receptor 4. (2020)  J Chem Inf Model, 60 (3): 1461-1468. [PMID:31944109]

  • From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9.
    Petrilli WL, Adam GC, Erdmann RS, Abeywickrema P, Agnani V, Ai X, Baysarowich J, Byrne N, Caldwell JP, Chang W et al.. From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9. (2020)  Cell Chem Biol, 27 (1): 32-40.e3. [PMID:31653597]

  • Structure of the M2 muscarinic receptor-β-arrestin complex in a lipid nanodisc.
    Staus DP, Hu H, Robertson MJ, Kleinhenz ALW, Wingler LM, Capel WD, Latorraca NR, Lefkowitz RJ, Skiniotis G. Structure of the M2 muscarinic receptor-β-arrestin complex in a lipid nanodisc. (2020)  Nature, 579 (7798): 297-302. [PMID:31945772]

  • Resting state structure of the hyperdepolarization activated two-pore channel 3.
    Dickinson MS, Myasnikov A, Eriksen J, Poweleit N, Stroud RM. Resting state structure of the hyperdepolarization activated two-pore channel 3. (2020)  Proc. Natl. Acad. Sci. U.S.A., 117 (4): 1988-1993. [PMID:31924746]

  • Impact of commonly used drugs on the composition and metabolic function of the gut microbiota.
    Vich Vila A, Collij V, Sanna S, Sinha T, Imhann F, Bourgonje AR, Mujagic Z, Jonkers DMAE, Masclee AAM, Fu J et al.. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. (2020)  Nat Commun, 11 (1): 362. [PMID:31953381]

  • New Chemical Modalities and Strategic Thinking in Early Drug Discovery.
    Blanco M-J, Gardiner KM. New Chemical Modalities and Strategic Thinking in Early Drug Discovery. (2020)  ACS Med Chem Lett,. DOI: 10.1021/acsmedchemlett.9b00582

  • Publisher Correction: Therapies for rare diseases: therapeutic modalities, progress and challenges ahead.
    Tambuyzer E, Vandendriessche B, Austin CP, Brooks PJ, Larsson K, Needleman KIM, Valentine J, Davies K, Groft SC, Preti R et al.. Publisher Correction: Therapies for rare diseases: therapeutic modalities, progress and challenges ahead. (2020)  Nat Rev Drug Discov, 19 (4): 291. [PMID:31913355]

  • Relative Selectivity of Covalent Inhibitors Requires Assessment of Inactivation Kinetics and Cellular Occupancy: A Case Study of Ibrutinib and Acalabrutinib.
    Hopper M, Gururaja T, Kinoshita T, Dean JP, Hill RJ, Mongan A. Relative Selectivity of Covalent Inhibitors Requires Assessment of Inactivation Kinetics and Cellular Occupancy: A Case Study of Ibrutinib and Acalabrutinib. (2020)  J. Pharmacol. Exp. Ther., 372 (3): 331-338. [PMID:31871305]

  • 2019 FDA drug approvals.
    Mullard A. 2019 FDA drug approvals. (2020)  Nat Rev Drug Discov, 19 (2): 79-84. [PMID:32020068]

  • Hot Topics: Cryo-EM structure of a selective T-type calcium channel blocker bound to the Cav3.1 voltage-gated calcium channel

    Comments by Jörg Striessnig, University of Innsbruck, Chair for NC-IUPHAR Subcommitee for Voltage-gated calcium channels, Liaison for NC-IUPHAR subcommittees on Voltage-gated ion channels

    Nieng Yan's group has now published the cryo-EM structure of the selective T-type Ca2+ channel blocker Z944 bound to the pore-forming α1-subunit of Cav3.1 T-type Ca2+ channels [85]. This nicely adds to recent publications reporting of the high-resolution structures of L-type Ca2+ channel blockers (nifedipine, nimodipine, amlodipine, verapamil, diltiazem) bound to the rabbit Cav1.1 skeletal muscle Ca2+ channel [84] and to the model Ca2+ channel CavAb (Ca2+-selectivity engineered into the bacterial homotetrameric Na+-channel NavAb; [66-67]). Read the full article on our blog

  • Fluorescent ligands: Bringing light to emerging GPCR paradigms.
    Soave M, Briddon SJ, Hill SJ, Stoddart LA. Fluorescent ligands: Bringing light to emerging GPCR paradigms. (2020)  Br. J. Pharmacol., 177 (5): 978-991. [PMID:31877233]

  • Methods to identify and optimize small molecules interacting with RNA (SMIRNAs).
    Ursu A, Vézina-Dawod S, Disney MD. Methods to identify and optimize small molecules interacting with RNA (SMIRNAs). (2019)  Drug Discov. Today, 24 (10): 2002-2016. [PMID:31356880]

  • The pharmacology and therapeutic applications of monoclonal antibodies.
    Castelli MS, McGonigle P, Hornby PJ. The pharmacology and therapeutic applications of monoclonal antibodies. (2019)  Pharmacol Res Perspect, 7 (6): e00535. [PMID:31859459]

  • PROTACs: great opportunities for academia and industry.
    Sun X, Gao H, Yang Y, He M, Wu Y, Song Y, Tong Y, Rao Y. PROTACs: great opportunities for academia and industry. (2019)  Signal Transduct Target Ther, 4: 64. [PMID:31885879]

  • December 2019


  • Structure of the Cardiac Sodium Channel.
    Jiang D, Shi H, Tonggu L, Gamal El-Din TM, Lenaeus MJ, Zhao Y, Yoshioka C, Zheng N, Catterall WA. Structure of the Cardiac Sodium Channel. (2020)  Cell, 180 (1): 122-134.e10. [PMID:31866066]

  • Hot Topics: Deciphering the crystal structure of the leukotriene receptor CysLT2 opens up for improved therapeutics

    Magnus Bäck, MD PhD, (@TransCardio), Karolinska Institutet and University Hospital, Stockholm, Sweden; Chairman NC-IUPHAR subcommittee on Leukotriene Receptors

    Leukotrienes are lipid mediators of inflammation, initially recognized for their role in asthma, but also having potent effects in for example cardiovascular and neurological diseases as well as in cancer. The initial pharmacological classification of leukotriene receptors based on antagonist selectivity in smooth muscle was shown to be valid at the gene and protein levels. Following the recent description of the CysLT1 receptor structure, Gusach et al. now describe the crystal structures of the CysLT2 receptor in complex with dual CysLT1/CysLT2 receptor antagonists [24].. Read the full article on our blog

  • GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infections.
    Flak MB, Koenis DS, Sobrino A, Smith J, Pistorius K, Palmas F, Dalli J. GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infections. (2020)  J. Clin. Invest., 130 (1): 359-373. [PMID:31793912]

  • Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists.
    Claff T, Yu J, Blais V, Patel N, Martin C, Wu L, Han GW, Holleran BJ, Van der Poorten O, White KL et al.. Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists. (2019)  Sci Adv, 5 (11): eaax9115. [PMID:31807708]

  • A complex structure of arrestin-2 bound to a G protein-coupled receptor.
    Yin W, Li Z, Jin M, Yin YL, de Waal PW, Pal K, Yin Y, Gao X, He Y, Gao J et al.. A complex structure of arrestin-2 bound to a G protein-coupled receptor. (2019)  Cell Res., 29 (12): 971-983. [PMID:31776446]

  • November 2019


  • Chemokine Receptor Crystal Structures: What Can Be Learned from Them?.
    Arimont M, Hoffmann C, de Graaf C, Leurs R. Chemokine Receptor Crystal Structures: What Can Be Learned from Them?. (2019)  Mol. Pharmacol., 96 (6): 765-777. [PMID:31266800]

  • The Druggability of Solute Carriers.
    Wang WW, Gallo L, Jadhav A, Hawkins R, Parker CG. The Druggability of Solute Carriers. (2020)  J. Med. Chem., 63 (8): 3834-3867. [PMID:31774679]

  • Hot Topics: New crystal structure of the muscarinic M5 receptor completes the set

    Comments by Fiona H. Marshall, Discovery Research UK, MSD (@aston_fm)

    Muscarinic receptors consist of 5 G protein-coupled receptors which along with nicotinic ion channels mediate the effects of acetylcholine. Despite years of research on the role of muscarinic receptors in the brain and periphery the Muscarinic M5 receptor has stood out in contrast to M1 -M4 as one which we know little about. The M5 receptor has a unique and unusual distribution in the brain being enriched in mid brain dopamine neurons and in the cerebellum. A lack of selective chemical tools has hampered our ability to study the function of the receptor. Now Vuckovic et al. [74] have solved the X-ray crystal structure of the M5 receptor in complex with the non-selective antagonist tiotropium in the presence of a conformational stabilizing mutation. Since tiotropium was also used to solve the structure of several other muscarinic receptors a direct comparison can be made across the subtypes which will enable the design of selective tool compounds. Significant progress has been made in utilizing crystal structures to design selective orthosteric and allosteric ligands at this family of receptors. This final structure completes the set of muscarinic receptor structures solved and hopefully will pave the way to further understanding of the biology of M5 and its role in disorders such as drug addiction and depression.. Read the full article on our blog

  • GPR75 receptor mediates 20-HETE-signaling and metastatic features of androgen-insensitive prostate cancer cells.
    Cárdenas S, Colombero C, Panelo L, Dakarapu R, Falck JR, Costas MA, Nowicki S. GPR75 receptor mediates 20-HETE-signaling and metastatic features of androgen-insensitive prostate cancer cells. (2020)  Biochim Biophys Acta Mol Cell Biol Lipids, 1865 (2): 158573. [PMID:31760076]

  • Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870.
    Zhou Y, Cao C, He L, Wang X, Zhang XC. Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870. (2019)  Elife, 8. [PMID:31750832]

  • The human secretome.
    Uhlén M, Karlsson MJ, Hober A, Svensson AS, Scheffel J, Kotol D, Zhong W, Tebani A, Strandberg L, Edfors F et al.. The human secretome. (2019)  Sci Signal, 12 (609). [PMID:31772123]

  • Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.
    Arboleda-Velasquez JF, Lopera F, O'Hare M, Delgado-Tirado S, Marino C, Chmielewska N, Saez-Torres KL, Amarnani D, Schultz AP, Sperling RA et al.. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. (2019)  Nat. Med., 25 (11): 1680-1683. [PMID:31686034]

  • In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice.
    Davidowitz EJ, Krishnamurthy PK, Lopez P, Jimenez H, Adrien L, Davies P, Moe JG. In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice. (2020)  J. Alzheimers Dis., 73 (1): 147-161. [PMID:31771053]

  • A New Alzheimer’s Approval in China
    Lowe D. A New Alzheimer’s Approval in China.  Science Trans Med: In The Pipeline, https://blogs.sciencemag.org/pipeline/archives/2019/11/04/a-new-alzheimers-approval-in-china
    Wang X, Sun G, Feng T, Zhang J, Huang X, Wang T, Xie Z, Chu X, Yang J, Wang H et al.. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer's disease progression. (2019)  Cell Res., 29 (10): 787-803. [PMID:31488882]

  • Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of N-Methylation for PI3Kδ Activity.
    Barnes L, Blaber H, Brooks DTK, Byers L, Buckley D, Byron ZC, Chilvers RG, Cochrane L, Cooney E, Damian HA et al.. Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of N-Methylation for PI3Kδ Activity. (2019)  J. Med. Chem., 62 (22): 10402-10422. [PMID:31647659]

  • An Alzheimer's-disease-protective APOE mutation.
    Zalocusky KA, Nelson MR, Huang Y. An Alzheimer's-disease-protective APOE mutation. (2019)  Nat. Med., 25 (11): 1648-1649. [PMID:31686033]

  • Discovery of ABBV/GLPG-3221, a Potent Corrector of CFTR for the Treatment of Cystic Fibrosis.
    Scanio MJC, Searle XB, Liu B, Koenig JR, Altenbach R, Gfesser GA, Bogdan A, Greszler S, Zhao G, Singh A et al.. Discovery of ABBV/GLPG-3221, a Potent Corrector of CFTR for the Treatment of Cystic Fibrosis. (2019)  ACS Med Chem Lett, 10 (11): 1543-1548. [PMID:31749908]

  • Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors.
    Foster SR, Hauser AS, Vedel L, Strachan RT, Huang XP, Gavin AC, Shah SD, Nayak AP, Haugaard-Kedström LM, Penn RB et al.. Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors. (2019)  Cell, 179 (4): 895-908.e21. [PMID:31675498]

  • October 2019


  • Structure of an allosteric modulator bound to the CB1 cannabinoid receptor.
    Shao Z, Yan W, Chapman K, Ramesh K, Ferrell AJ, Yin J, Wang X, Xu Q, Rosenbaum DM. Structure of an allosteric modulator bound to the CB1 cannabinoid receptor. (2019)  Nat. Chem. Biol., 15 (12): 1199-1205. [PMID:31659318]

  • Structural basis of species-selective antagonist binding to the succinate receptor.
    Haffke M, Fehlmann D, Rummel G, Boivineau J, Duckely M, Gommermann N, Cotesta S, Sirockin F, Freuler F, Littlewood-Evans A et al.. Structural basis of species-selective antagonist binding to the succinate receptor. (2019)  Nature, 574 (7779): 581-585. [PMID:31645725]

  • A Point of Inflection and Reflection on Systems Chemical Biology.
    Johnson EO, Hung DT. A Point of Inflection and Reflection on Systems Chemical Biology. (2019)  ACS Chem. Biol., 14 (12): 2497-2511. [PMID:31613592]

  • A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor.
    Dekan Z, Sianati S, Yousuf A, Sutcliffe KJ, Gillis A, Mallet C, Singh P, Jin AH, Wang AM, Mohammadi SA et al.. A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor. (2019)  Proc. Natl. Acad. Sci. U.S.A., 116 (44): 22353-22358. [PMID:31611414]

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

    Comments by Dr. 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., [42] 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

  • September 2019


  • A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity.
    Tran KT, Pallesen JS, Solbak SMØ, Narayanan D, Baig A, Zang J, Aguayo-Orozco A, Carmona RMC, Garcia AD, Bach A. A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity. (2019)  J. Med. Chem., 62 (17): 8028-8052. [PMID:31411465]

  • Advances and Challenges in Rational Drug Design for SLCs.
    Garibsingh RA, Schlessinger A. Advances and Challenges in Rational Drug Design for SLCs. (2019)  Trends Pharmacol. Sci., 40 (10): 790-800. [PMID:31519459]

  • Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database.
    Nguengang Wakap S, Lambert DM, Olry A, Rodwell C, Gueydan C, Lanneau V, Murphy D, Le Cam Y, Rath A. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. (2020)  Eur. J. Hum. Genet., 28 (2): 165-173. [PMID:31527858]

  • August 2019


  • Single-Cell Analysis of Human Mononuclear Phagocytes Reveals Subset-Defining Markers and Identifies Circulating Inflammatory Dendritic Cells.
    Dutertre CA, Becht E, Irac SE, Khalilnezhad A, Narang V, Khalilnezhad S, Ng PY, van den Hoogen LL, Leong JY, Lee B et al.. Single-Cell Analysis of Human Mononuclear Phagocytes Reveals Subset-Defining Markers and Identifies Circulating Inflammatory Dendritic Cells. (2019)  Immunity, 51 (3): 573-589.e8. [PMID:31474513]

  • SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action.
    Dedic N, Jones PG, Hopkins SC, Lew R, Shao L, Campbell JE, Spear KL, Large TH, Campbell UC, Hanania T et al.. SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action. (2019)  J. Pharmacol. Exp. Ther., 371 (1): 1-14. [PMID:31371483]

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

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

    The cross-talk between different G protein-coupled receptor signal-transduction pathways is an intriguing concept with important physiological implications (Selbie et al. 1998). A recent study by Wang et al. 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 (Vedel et al. 2019 [72]). These findings implicate GPR139 as a potential target for increasing opioid safety.. Read the full article on our blog

  • Over 1000 genetic loci influencing blood pressure with multiple systems and tissues implicated.
    Cabrera CP, Ng FL, Nicholls HL, Gupta A, Barnes MR, Munroe PB, Caulfield MJ. Over 1000 genetic loci influencing blood pressure with multiple systems and tissues implicated. (2019)  Hum. Mol. Genet., 28 (R2): R151-R161. [PMID:31411675]

  • Large-Scale Analyses of Human Microbiomes Reveal Thousands of Small, Novel Genes.
    Sberro H, Fremin BJ, Zlitni S, Edfors F, Greenfield N, Snyder MP, Pavlopoulos GA, Kyrpides NC, Bhatt AS. Large-Scale Analyses of Human Microbiomes Reveal Thousands of Small, Novel Genes. (2019)  Cell, 178 (5): 1245-1259.e14. [PMID:31402174]

  • Hot Topics: 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 (Wisedchaisri et al. 2019 [79]). 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

  • Identification of a novel allosteric GLP-1R antagonist HTL26119 using structure- based drug design.
    O'Brien A, Andrews SP, Baig AH, Bortolato A, Brown AJH, Brown GA, Brown SH, Christopher JA, Congreve M, Cooke RM et al.. Identification of a novel allosteric GLP-1R antagonist HTL26119 using structure- based drug design. (2019)  Bioorg. Med. Chem. Lett., 29 (20): 126611. [PMID:31447084]

  • Visualization of drug target interactions in the contexts of pathways and networks with ReactomeFIViz.
    Blucher AS, McWeeney SK, Stein L, Wu G. Visualization of drug target interactions in the contexts of pathways and networks with ReactomeFIViz. (2019)  F1000Res, 8: 908. [PMID:31372215]

  • Structure and mechanism of the cation-chloride cotransporter NKCC1.
    Chew TA, Orlando BJ, Zhang J, Latorraca NR, Wang A, Hollingsworth SA, Chen DH, Dror RO, Liao M, Feng L. Structure and mechanism of the cation-chloride cotransporter NKCC1. (2019)  Nature, 572 (7770): 488-492. [PMID:31367042]

  • Building a Hybrid Physical-Statistical Classifier for Predicting the Effect of Variants Related to Protein-Drug Interactions.
    Wang B, Yan C, Lou S, Emani P, Li B, Xu M, Kong X, Meyerson W, Yang YT, Lee D et al.. Building a Hybrid Physical-Statistical Classifier for Predicting the Effect of Variants Related to Protein-Drug Interactions. (2019)  Structure, 27 (9): 1469-1481.e3. [PMID:31279629]

  • Revisiting the classification of adhesion GPCRs.
    Scholz N, Langenhan T, Schöneberg T. Revisiting the classification of adhesion GPCRs. (2019)  Ann. N. Y. Acad. Sci., 1456 (1): 80-95. [PMID:31365134]