title: Modeling Local Structural Rearrangements Using FEP/REST: Application to Relative Binding Affinity Predictions of CDK2 Inhibitors.
abstract: Accurate and reliable calculation of protein-ligand binding affinities remains a hotbed of computer-aided drug design research. Despite the potentially large impact FEP (free energy perturbation) may have in drug design projects, practical applications of FEP in industrial contexts have been limited. In this work, we use a recently developed method, FEP/REST (free energy perturbation/replica exchange with solute tempering), to calculate the relative binding affinities for a set of congeneric ligands binding to the CDK2 receptor. We compare the FEP/REST results with traditional FEP/MD (molecular dynamics) results and MM/GBSA (molecular mechanics/Generalized Born Surface Area model) results and examine why FEP/REST performed notably better than these other methods, as well as why certain ligand mutations lead to large increases of the binding affinity while others do not. We also introduce a mathematical framework for assessing the consistency and reliability of the calculations using cycle closures in FEP mutation paths.
authors.affiliation: Schrodinger, 120 West 45st Street, New York, New York 10036, United States.
authors.forename: Lingle
authors.initials: L
authors.lastname: Wang
authors.affiliation: Schrodinger, 120 West 45st Street, New York, New York 10036, United States.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Schrodinger, 120 West 45st Street, New York, New York 10036, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Knight
authors.affiliation: Schrodinger, 120 West 45st Street, New York, New York 10036, United States.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Schrodinger, 120 West 45st Street, New York, New York 10036, United States.
authors.forename: Byungchan
authors.initials: B
authors.lastname: Kim
authors.affiliation: Schrodinger, 120 West 45st Street, New York, New York 10036, United States.
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman
authors.affiliation: Schrodinger, 120 West 45st Street, New York, New York 10036, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Shelley
authors.affiliation: Schrodinger, 120 West 45st Street, New York, New York 10036, United States.
authors.forename: Teng
authors.initials: T
authors.lastname: Lin
authors.affiliation: Schrodinger, 120 West 45st Street, New York, New York 10036, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Abel