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Mapping the druggable allosteric space of G-protein coupled receptors: a fragment-based molecular dynamics approach.

Abstract：

:To address the problem of specificity in G-protein coupled receptor (GPCR) drug discovery, there has been tremendous recent interest in allosteric drugs that bind at sites topographically distinct from the orthosteric site. Unfortunately, structure-based drug design of allosteric GPCR ligands has been frustrated by the paucity of structural data for allosteric binding sites, making a strong case for predictive computational methods. In this work, we map the surfaces of the beta1 (beta1AR) and beta2 (beta2AR) adrenergic receptor structures to detect a series of five potentially druggable allosteric sites. We employ the FTMAP algorithm to identify 'hot spots' with affinity for a variety of organic probe molecules corresponding to drug fragments. Our work is distinguished by an ensemble-based approach, whereby we map diverse receptor conformations taken from molecular dynamics (MD) simulations totaling approximately 0.5 micros. Our results reveal distinct pockets formed at both solvent-exposed and lipid-exposed cavities, which we interpret in light of experimental data and which may constitute novel targets for GPCR drug discovery. This mapping data can now serve to drive a combination of fragment-based and virtual screening approaches for the discovery of small molecules that bind at these sites and which may offer highly selective therapies.

journal_name

Chem Biol Drug Des

journal_title

Chemical biology & drug design

authors

Ivetac A,McCammon JA

doi

10.1111/j.1747-0285.2010.01012.x

subject

Has Abstract

pub_date

2010-09-01 00:00:00

pages

201-17

issue

3

eissn

1747-0277

issn

1747-0285

pii

JPP1012

journal_volume

76

pub_type

杂志文章

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