title: WScore: A Flexible and Accurate Treatment of Explicit Water Molecules in Ligand-Receptor Docking.
abstract: We have developed a new methodology for protein-ligand docking and scoring, WScore, incorporating a flexible description of explicit water molecules. The locations and thermodynamics of the waters are derived from a WaterMap molecular dynamics simulation. The water structure is employed to provide an atomic level description of ligand and protein desolvation. WScore also contains a detailed model for localized ligand and protein strain energy and integrates an MM-GBSA scoring component with these terms to assess delocalized strain of the complex. Ensemble docking is used to take into account induced fit effects on the receptor conformation, and protein reorganization free energies are assigned via fitting to experimental data. The performance of the method is evaluated for pose prediction, rank ordering of self-docked complexes, and enrichment in virtual screening, using a large data set of PDB complexes and compared with the Glide SP and Glide XP models; significant improvements are obtained.
authors.affiliation: Schrödinger, Inc. , 101 SW Main Street, Portland Oregon 97204, United States.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Murphy
authors.affiliation: Schrödinger, Inc. , 101 SW Main Street, Portland Oregon 97204, United States.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Repasky
authors.affiliation: Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Greenwood
authors.affiliation: Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Ivan
authors.initials: I
authors.lastname: Tubert-Brohman
authors.affiliation: Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Jerome
authors.affiliation: Schrödinger , Plot no. 573, Road no. 1, Jubilee Hills, Hyderabad 5000096, Telangana, India.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Annabhimoju
authors.affiliation: Schrödinger, Inc. , 101 SW Main Street, Portland Oregon 97204, United States.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Boyles
authors.affiliation: Schrödinger, Inc. , 101 SW Main Street, Portland Oregon 97204, United States.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Schmitz
authors.affiliation: Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Abel
authors.affiliation: Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Ramy
authors.initials: R
authors.lastname: Farid
authors.affiliation: Department of Chemistry, Columbia University , New York, 3000 Broadway, MC 3110, New York 10036, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friesner
mesh_terms: D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D011956:Receptors, Cell Surface / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D008024:Ligands; D011956:Receptors, Cell Surface; D014867:Water