John D. McCorvy, PhD
- Cell Biology, Neurobiology & Anatomy
PhD, Medicinal Chemistry and Molecular Pharmacology, Purdue University, 2012
BA, Biochemistry and Psychology, Texas Tech University, 2005
- Antipsychotic Agents
- Binding Sites
- Central Nervous System Stimulants
- Crystallography, X-Ray
- Dopamine Agonists
- Drug Design
- Drug Discovery
- Lysergic Acid Diethylamide
The McCorvy lab studies G protein-coupled receptor (GPCR) recognition and signaling involved in various psychoactive and physiological effects present in human disease, with an emphasis on psychedelic, antipsychotic, and antidepressant drug action. In particular, the lab studies the phenomenon known as “biased signaling” or “functional selectivity”, whereby drugs for any given receptor can exhibit a spectrum of signal transduction pathways, G protein-dependent (e.g. Gq, Gs, Gi) or G protein-independent (e.g. β-arrestin). The ultimate aim of the lab is to profile, delineate, and exploit key signal transduction pathways using a combination of chemical biology, structure-based drug design, medicinal chemistry and high-throughput screening (HTS) technologies.
With the discovery of GPCR functional selectivity, high-throughput screening (HTS) and virtual ligand screening (VLS) technologies have yielded novel biased ligands for the µ-opioid receptor (Manglik et al. Nature 2015), dopamine D2 (Chen, McCorvy et al. J Med Chem 2016) and D4 (Wang et al. Science 2017), and serotonin 5-HT2C (Cheng, McCorvy et al. J Med Chem 2016) receptors. An on-going question, however, is exactly how biased ligands translate information to the receptor binding pocket to prefer or engage specific intracellular effectors (e.g. G proteins, β-arrestins) leading to ligand bias. Using a structure-based approach, major determinants of ligand bias in the binding pocket (e.g. extracellular loop 2) have been discovered and elucidated with the structure of LSD in the 5-HT2B receptor (Wacker, Wang, McCorvy et al. Cell 2017), an area exploited for other aminergic GPCRs (McCorvy, Butler et al. Nature Chemical Biology 2018) to yield novel β-arrestin biased ligands as potential antipsychotics and antidepressants, devoid of hallucinogenic potential. Current mapping of key binding pocket areas of GPCRs has led to the identification of other putative ‘allosteric sites’ responsible for ligand bias for the 5-HT2B receptor (McCorvy, Wacker, Wang et al. Nature Structural and Molecular Biology 2018). These semi-conserved structural motifs incorporating extracellular regions of the binding pocket can be exploited for a host of new pharmacological probes (biased positive allosteric modulators) to elucidate structural mechanisms ultimately responsible for ligand bias. New probes and understanding into the structural determinants of GPCR biased signaling will serve as a blueprint for a new generation of novel rationally-designed biased small molecule therapeutics for a host of diseases.
Areas of focus
Profiling of Psychoactive Drugs for Biased Signaling at Aminergic GPCRs
A key aim of the lab is to “uncover” biased signaling profiles at a plethora of aminergic (serotonin, dopamine, and adrenergic) GPCRs. Typically, drugs such as antipsychotics and antidepressants have several targets, a phenomenon known as “polypharmacology”, including acting as mixed agonists or antagonists at a host of aminergic receptors (D2, 5-HT2A, 5-HT2C, α2A), many at which can lead to serious side-effects (5-HT2B and cardiac valvulopathy). However, not all signal transduction pathways for these receptors have been extensively profiled for ligand bias, including a key non-canonical effector, β-arrestin, which can cause desensitization, internalization, and G protein-independent signaling in a time-dependent manner. Therefore, by understanding GPCR signal transduction kinetics, “signatures” of psychoactive drugs that lead to side-effects can be identified, exploited or avoided for safer therapeutics for depression, schizophrenia, and mood disorders (see McCorvy et al. J Psychopharmacology 2016).
Determining Biased Ligand Recognition Structure-Function Relationships
With the recent explosion in GPCR structural biology, a host of techniques are available to elucidate distinct binding modes that lead to biased agonism (see McCorvy, Wacker, Wang et al. Nature Structural and Molecular Biology 2018). One of the best approaches is to use GPCR structures to pair ligand structure-activity-relationships (SAR) with pharmacological assays measuring several signaling pathways to construct structure-functional selectivity relationships (SFSRs) and to identify the key chemical substituent(s) that ‘direct’ biased signaling via binding pocket residue engagement. Using extensive mutagenesis and analog design, molecular determinants of biased agonism can be revealed to understand binding poses that lead to switch in effector (G proteins, β-arrestin) preference.
Design of novel ligands or probes with a new mechanism of action
Identification of key GPCR motifs (e.g. EL2, figure 3) important for directing effector engagement has been critical for the design of novel probes as potential biased therapeutics. A key area of interest is using synthetic drug design to target regions specific for β-arrestin bias (McCorvy, Butler et al. Nature Chemical Biology 2018), or effectively to avoid them using a constructed drug design template applicable for aminergic GPCRs. Together with identifying conserved binding mode areas of the receptor, a complex ‘biased’ polypharmacology (Peng, McCorvy et al. Cell 2018) can be constructed to yield G protein or β-arrestin bias across a spectrum of important aminergic GPCRs. In addition, potential allosteric sites have been identified as an area to develop new ‘biased’ positive or negative allosteric modulators.
(Kleist AB, Jenjak S, Sente A, Laskowski LJ, Szpakowska M, Calkins MM, Anderson EI, McNally LM, Heukers R, Bobkov V, Peterson FC, Thomas MA, Chevigné A, Smit MJ, McCorvy JD, Babu MM, Volkman BF.) Science. 2022 Jul 08;377(6602):222-228 PMID: 35857540 PMCID: PMC9574477 SCOPUS ID: 2-s2.0-85133822505 07/21/2022
(Orr MJ, Cao AB, Wang CT, Gaisin A, Csakai A, Friswold AP, Meltzer HY, McCorvy JD, Scheidt KA.) ACS Med Chem Lett. 2022 Apr 14;13(4):648-657 PMID: 35450369 PMCID: PMC9014500 04/23/2022
(Rudin D, McCorvy JD, Glatfelter GC, Luethi D, Szöllősi D, Ljubišić T, Kavanagh PV, Dowling G, Holy M, Jaentsch K, Walther D, Brandt SD, Stockner T, Baumann MH, Halberstadt AL, Sitte HH.) Neuropsychopharmacology. 2022 Mar;47(4):914-923 PMID: 34750565 PMCID: PMC8882185 11/10/2021
(Cao C, Kang HJ, Singh I, Chen H, Zhang C, Ye W, Hayes BW, Liu J, Gumpper RH, Bender BJ, Slocum ST, Krumm BE, Lansu K, McCorvy JD, Kroeze WK, English JG, DiBerto JF, Olsen RHJ, Huang XP, Zhang S, Liu Y, Kim K, Karpiak J, Jan LY, Abraham SN, Jin J, Shoichet BK, Fay JF, Roth BL.) Nature. 2021 Dec;600(7887):170-175 PMID: 34789874 PMCID: PMC9150435 11/19/2021
(Sadler KE, Moehring F, Shiers SI, Laskowski LJ, Mikesell AR, Plautz ZR, Brezinski AN, Mecca CM, Dussor G, Price TJ, McCorvy JD, Stucky CL.) Sci Transl Med. 2021 May 26;13(595) PMID: 34039739 PMCID: PMC8923002 SCOPUS ID: 2-s2.0-85106954302 05/28/2021
(Klein AK, Chatha M, Laskowski LJ, Anderson EI, Brandt SD, Chapman SJ, McCorvy JD, Halberstadt AL.) ACS Pharmacol Transl Sci. 2021 Apr 09;4(2):533-542 PMID: 33860183 PMCID: PMC8033608 04/17/2021
(Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, Vargas MV, McCarroll MN, Taylor JC, Myers-Turnbull D, Liu T, Yaghoobi B, Laskowski LJ, Anderson EI, Zhang G, Viswanathan J, Brown BM, Tjia M, Dunlap LE, Rabow ZT, Fiehn O, Wulff H, McCorvy JD, Lein PJ, Kokel D, Ron D, Peters J, Zuo Y, Olson DE.) Nature. 2021 Jan;589(7842):474-479 PMID: 33299186 PMCID: PMC7874389 12/11/2020
(Wedemeyer MJ, Mahn SA, Getschman AE, Crawford KS, Peterson FC, Marchese A, McCorvy JD, Volkman BF.) J Biol Chem. 2020 Oct 02;295(40):13927-13939 PMID: 32788219 PMCID: PMC7535910 SCOPUS ID: 2-s2.0-85092681956 08/14/2020
(Olsen RHJ, DiBerto JF, English JG, Glaudin AM, Krumm BE, Slocum ST, Che T, Gavin AC, McCorvy JD, Roth BL, Strachan RT.) Nat Chem Biol. 2020 Aug;16(8):841-849 PMID: 32367019 PMCID: PMC7648517 05/06/2020
(Patel N, Huang XP, Grandner JM, Johansson LC, Stauch B, McCorvy JD, Liu Y, Roth B, Katritch V.) Elife. 2020 Mar 02;9 PMID: 32118583 PMCID: PMC7080406 03/03/2020
(Stein RM, Kang HJ, McCorvy JD, Glatfelter GC, Jones AJ, Che T, Slocum S, Huang XP, Savych O, Moroz YS, Stauch B, Johansson LC, Cherezov V, Kenakin T, Irwin JJ, Shoichet BK, Roth BL, Dubocovich ML.) Nature. 2020 Mar;579(7800):609-614 PMID: 32040955 PMCID: PMC7134359 02/11/2020
(Sherwood AM, Halberstadt AL, Klein AK, McCorvy JD, Kaylo KW, Kargbo RB, Meisenheimer P.) J Nat Prod. 2020 Feb 28;83(2):461-467 PMID: 32077284 02/23/2020