Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery

Xin Qiao; Xiaolong Li; Mingyang Zhang; Ning Liu; Yanmei Wu; Shaoyong Lu; Ting Chen

doi:10.1016/j.phrs.2024.107574

Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery

Pharmacol Res. 2025 Jan 2:107574. doi: 10.1016/j.phrs.2024.107574. Online ahead of print.

Authors

Xin Qiao¹, Xiaolong Li², Mingyang Zhang³, Ning Liu⁴, Yanmei Wu⁵, Shaoyong Lu⁶, Ting Chen⁷

Affiliations

¹ Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Center, School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
² Department of Orthopedics, Changhai Hospital, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
³ Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
⁴ Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Center, School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
⁵ Department of General Surgery, Changhai Hospital, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China. Electronic address: [email protected].
⁶ Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Center, School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China. Electronic address: [email protected].
⁷ Department of Cardiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China. Electronic address: [email protected].

PMID: 39755133
DOI: 10.1016/j.phrs.2024.107574

Abstract

G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors and are highly effective targets for therapeutic drugs. GPCRs couple different downstream effectors, including G proteins (such as Gi/o, Gs, G12, and Gq) and β-arrestins (such as β-arrestin 1 and β-arrestin 2) to mediate diverse cellular and physiological responses. Biased signaling allows for the specific activation of certain pathways from the full range of receptors' signaling capabilities. Targeting more variable allosteric sites, which are spatially different from the highly conserved orthosteric sites, represents a novel approach in biased GPCR drug discovery, leading to innovative strategies for targeting GPCRs. Notably, the emergence of cryptic allosteric sites on GPCRs has expanded the repertoire of available drug targets and improved receptor subtype selectivity. Here, we conduct a summary of recent progress in the structural determination of cryptic allosteric sites on GPCRs and elucidate the biased signaling mechanisms induced by allosteric modulators. Additionally, we discuss means to identify cryptic allosteric sites and design biased allosteric modulators based on cryptic allosteric sites through structure-based drug design, which is an advanced pharmacotherapeutic approach for treating GPCR-associated diseases.

Keywords: Allosteric modulators; Biased signaling; Cryptic allosteric sites; Drug design; G protein-coupled receptors.

Publication types

Review