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Covalent allosteric modulation: An emerging strategy for GPCRs drug discovery.

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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Bian Y,Jun JJ,Cuyler J,Xie XQ

doi

10.1016/j.ejmech.2020.112690

subject

Has Abstract

pub_date

2020-11-15 00:00:00

pages

112690

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(20)30662-0

journal_volume

206

pub_type

杂志文章,评审

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