title: Accurate Modeling of Scaffold Hopping Transformations in Drug Discovery.
abstract: The accurate prediction of protein-ligand binding free energies remains a significant challenge of central importance in computational biophysics and structure-based drug design. Multiple recent advances including the development of greatly improved protein and ligand molecular mechanics force fields, more efficient enhanced sampling methods, and low-cost powerful GPU computing clusters have enabled accurate and reliable predictions of relative protein-ligand binding free energies through the free energy perturbation (FEP) methods. However, the existing FEP methods can only be used to calculate the relative binding free energies for R-group modifications or single-atom modifications and cannot be used to efficiently evaluate scaffold hopping modifications to a lead molecule. Scaffold hopping or core hopping, a very common design strategy in drug discovery projects, is critical not only in the early stages of a discovery campaign where novel active matter must be identified but also in lead optimization where the resolution of a variety of ADME/Tox problems may require identification of a novel core structure. In this paper, we introduce a method that enables theoretically rigorous, yet computationally tractable, relative protein-ligand binding free energy calculations to be pursued for scaffold hopping modifications. We apply the method to six pharmaceutically interesting cases where diverse types of scaffold hopping modifications were required to identify the drug molecules ultimately sent into the clinic. For these six diverse cases, the predicted binding affinities were in close agreement with experiment, demonstrating the wide applicability and the significant impact Core Hopping FEP may provide in drug discovery projects.
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Lingle
authors.identifier: 0000-0002-8170-6798
authors.initials: L
authors.lastname: Wang
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Byungchan
authors.initials: B
authors.lastname: Kim
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: David N
authors.initials: DN
authors.lastname: LeBard
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Dan
authors.initials: D
authors.lastname: Wandschneider
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Mike
authors.initials: M
authors.lastname: Beachy
authors.affiliation: Department of Chemistry, Columbia University , 3000 Broadway, New York, New York 10027, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friesner
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Abel
mesh_terms: D055808:Drug Discovery; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011506:Proteins