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Mapping the Druggable Allosteric Space of G‐Protein Coupled Receptors: a Fragment‐Based Molecular Dynamics Approach
Author(s) -
Ivetac Anthony,
Andrew McCammon J.
Publication year - 2010
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2010.01012.x
Subject(s) - druggability , allosteric regulation , drug discovery , virtual screening , g protein coupled receptor , computational biology , small molecule , molecular dynamics , chemical space , chemistry , receptor , biology , biochemistry , computational chemistry , gene
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 β 1 (β 1 AR) and β 2 (β 2 AR) 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 μs. 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.