title: Guiding lead optimization with GPCR structure modeling and molecular dynamics.
abstract: 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.
authors.affiliation: Evotec Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK. Electronic address: Alexander.Heifetz@Evotec.com.
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
authors.affiliation: Evotec Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK. Electronic address: Tim.James@Evotec.com.
authors.forename: Tim
authors.initials: T
authors.lastname: James
authors.affiliation: Evotec Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.
authors.forename: Inaki
authors.initials: I
authors.lastname: Morao
authors.affiliation: Evotec Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bodkin
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Biggin
mesh_terms: D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled