title: Docking and Virtual Screening Strategies for GPCR Drug Discovery.
abstract: Progress in structure determination of G protein-coupled receptors (GPCRs) has made it possible to apply structure-based drug design (SBDD) methods to this pharmaceutically important target class. The quality of GPCR structures available for SBDD projects fall on a spectrum ranging from high resolution crystal structures (<2 Å), where all water molecules in the binding pocket are resolved, to lower resolution (>3 Å) where some protein residues are not resolved, and finally to homology models that are built using distantly related templates. Each GPCR project involves a distinct set of opportunities and challenges, and requires different approaches to model the interaction between the receptor and the ligands. In this review we will discuss docking and virtual screening to GPCRs, and highlight several refinement and post-processing steps that can be used to improve the accuracy of these calculations. Several examples are discussed that illustrate specific steps that can be taken to improve upon the docking and virtual screening accuracy. While GPCRs are a unique target class, many of the methods and strategies outlined in this review are general and therefore applicable to other protein families.
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, NY, 10036, USA, thijs.beuming@schrodinger.com.
authors.forename: Thijs
authors.initials: T
authors.lastname: Beuming
authors.forename: Bart
authors.initials: B
authors.lastname: Lenselink
authors.forename: Daniele
authors.initials: D
authors.lastname: Pala
authors.forename: Fiona
authors.initials: F
authors.lastname: McRobb
authors.forename: Matt
authors.initials: M
authors.lastname: Repasky
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman
mesh_terms: D004353:Drug Evaluation, Preclinical / Q000379:methods*; D054314:Drug Inverse Agonism; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation / Q000379:methods*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D014584:User-Computer Interface; D014867:Water / Q000737:chemistry
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D014867:Water