Pharmacologically targeting intracellular allosteric sites of GPCRs for drug discovery

Drug Discov Today. 2023 Oct 16:103803. doi: 10.1016/j.drudis.2023.103803. Online ahead of print.ABSTRACTG-protein-coupled receptors (GPCRs) are a family of cell surface proteins that can sense a variety of extracellular stimuli and mediate multiple signaling transduction pathways involved in human physiology. Recent advances in GPCR structural biology have revealed a relatively conserved intracellular allosteric site in multiple GPCRs, which can be utilized to modulate receptors from the inside. This novel intracellular site partially overlaps with the G-protein and β-arrestin coupling sites, providing a novel avenue for biological intervention. Here, we review evidence available for GPCR structures complexed with intracellular small-molecule allosteric modulators, elucidating drug-target interactions and allosteric mechanisms. Moreover, we highlight the potential of intracellular allosteric modulators in achieving biased signaling, which provides insights into biased allosteric mechanisms. Teaser: We review the high-resolution structural advances and allosteric pharmacology of small-molecule modulators targeting the GPCR intracellular signaling protein interface.PMID:37852356 | DOI:10.1016/j.drudis.2023.103803
Source: Drug Discovery Today - Category: Drugs & Pharmacology Authors: Source Type: research