title: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA. aivetac@mccammon.ucsd.edu
authors.forename: Anthony
authors.initials: A
authors.lastname: Ivetac
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000465:Algorithms; D000495:Allosteric Site; D055808:Drug Discovery / Q000379:methods*; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled