Molecular Mechanism of Action of GPR91 Agonists and Antagonists: Insights from Molecular Dynamics Simulation

Abstract

G protein-coupled receptor 91 (GPR91) has garnered widespread attention as a prospective therapeutic target for metabolic diseases. However, no structural data for human GPR91 (hGPR91) and detailed molecular mechanism of action (MOA) of GPR91 have been reported, with reported compounds targeting GPR91 limited. In this study, hGPR91 structures were constructed through homology modeling. High-affinity agonist compound 31 and antagonist NF-58-EJ40 were selected for investigation. By molecular dynamics (MD) simulations, we have elucidated MOA of GPR91 agonists and antagonists for the first time. We identified the crucial role of the D174FASSG sequence, the L65^2.46SVSD^2.50 sequence and the N64^2.45-W147^4.50 in maintaining GPR91’s inactive state conformation. Agonist binding disrupted constraints mediated by the aforementioned sequence, which led to significant outward movements of transmembrane helixes (TMs) and repositioning of intracellular loop2 (ICL2) and ICL3, thereby forming an expanded cavity for G proteins binding. Furthermore, the pivotal role of the dicarboxylic acid structure of agonists in initiating signal transduction was confirmed. In contrast, antagonist binding stabilized these conformational constraints, resulting in relatively minor movements of TMs that were insufficient to generate a binding cavity large enough to accommodate the G protein. Clarifying MOA of GPR91 agonists and antagonists is crucial for guiding the design of relevant drugs.

Keywords

G protein-coupled receptor 91 (GPR91) / Mechanism of action (MOA) / Agonist / Antagonist / Molecular dynamics (MD)

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