期刊
CHEMICAL BIOLOGY & DRUG DESIGN
卷 76, 期 3, 页码 201-217出版社
WILEY
DOI: 10.1111/j.1747-0285.2010.01012.x
关键词
allosteric; docking; fragment-based; GPCR; molecular dynamics
资金
- National Science Foundation
- National Institutes of Health
- Howard Hughes Medical Institute
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 beta(1) (beta(1)AR) and beta(2) (beta(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 mu s. 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.
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