John D. McCorvy, PhD

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.

Recent Discoveries
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-HT_2C (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-HT_2B 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-HT_2B 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-HT_2A, 5-HT_2C, α_2A), many at which can lead to serious side-effects (5-HT_2B 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.