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G-protein coupled receptor (GPCR) modeling approaches are widely used in the hit-to-lead and lead optimization stages of drug discovery. Modern protocols that involve molecular dynamics simulation can address key issues such as the free energy of binding (affinity), ligand-induced GPCR flexibility, ligand binding kinetics, conserved water positions and their role in ligand binding and the effects of mutations. The goals of these calculations are to predict the structures of the complexes between existing ligands and their receptors, to understand the key interactions and to utilize these insights in the design of new molecules with improved binding, selectivity or other pharmacological properties. In this review we present a brief survey of various computational approaches illustrated through a hierarchical GPCR modeling protocol and its prospective application in three industrial drug discovery projects.

Original publication

DOI

10.1016/j.coph.2016.06.004

Type

Journal article

Journal

Curr Opin Pharmacol

Publication Date

10/2016

Volume

30

Pages

14 - 21

Keywords

Drug Design, Drug Discovery, Humans, Ligands, Molecular Dynamics Simulation, Protein Binding, Receptors, G-Protein-Coupled