Covalent Allosteric Modulation: An Emerging Strategy for GPCRs Drug Discovery

Overview

Journal Eur J Med Chem

Specialty Chemistry

Date 2020 Aug 21

PMID 32818870

Citations 14

Authors

Yuemin Bian

Jaden Jungho Jun

Jacob Cuyler

Xiang-Qun Xie

Affiliations

Soon will be listed here.

Abstract

Designing covalent allosteric modulators brings new opportunities to the field of drug discovery towards G-protein-coupled receptors (GPCRs). Targeting an allosteric binding pocket can allow a modulator to have protein subtype selectivity and low drug resistance. Utilizing covalent warheads further enables the modulator to increase the binding potency and extend the duration of action. This review starts with GPCR allosteric modulation to discuss the structural biology of allosteric binding pockets, the different types of allosteric modulators, as well as the advantages of employing allosteric modulation. This is followed by a discussion on covalent modulators to clarify how covalent ligands can benefit the receptor modulation and to illustrate moieties that can commonly be used as covalent warheads. Finally, case studies are presented on designing class A, B, and C GPCR covalent allosteric modulators to demonstrate successful stories on combining allosteric modulation and covalent binding. Limitations and future perspectives are also covered.

Citing Articles

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