title: Relative Binding Free Energy Calculations Applied to Protein Homology Models.
abstract: A significant challenge and potential high-value application of computer-aided drug design is the accurate prediction of protein-ligand binding affinities. Free energy perturbation (FEP) using molecular dynamics (MD) sampling is among the most suitable approaches to achieve accurate binding free energy predictions, due to the rigorous statistical framework of the methodology, correct representation of the energetics, and thorough treatment of the important degrees of freedom in the system (including explicit waters). Recent advances in sampling methods and force fields coupled with vast increases in computational resources have made FEP a viable technology to drive hit-to-lead and lead optimization, allowing for more efficient cycles of medicinal chemistry and the possibility to explore much larger chemical spaces. However, previous FEP applications have focused on systems with high-resolution crystal structures of the target as starting points-something that is not always available in drug discovery projects. As such, the ability to apply FEP on homology models would greatly expand the domain of applicability of FEP in drug discovery. In this work we apply a particular implementation of FEP, called FEP+, on congeneric ligand series binding to four diverse targets: a kinase (Tyk2), an epigenetic bromodomain (BRD4), a transmembrane GPCR (A2A), and a protein-protein interaction interface (BCL-2 family protein MCL-1). We apply FEP+ using both crystal structures and homology models as starting points and find that the performance using homology models is generally on a par with the results when using crystal structures. The robustness of the calculations to structural variations in the input models can likely be attributed to the conformational sampling in the molecular dynamics simulations, which allows the modeled receptor to adapt to the "real" conformation for each ligand in the series. This work exemplifies the advantages of using all-atom simulation methods with full system flexibility and offers promise for the general application of FEP to homology models, although additional validation studies should be performed to further understand the limitations of the method and the scenarios where FEP will work best.
authors.affiliation: Schrödinger GmbH , Dynamostraße 13, 68165 Mannheim, Germany.
authors.forename: Daniel
authors.identifier: 0000-0002-8460-7867
authors.initials: D
authors.lastname: Cappel
authors.affiliation: Schrodinger Inc. , 120 W 45th Street, New York, New York 10036, United States.
authors.forename: Michelle Lynn
authors.initials: ML
authors.lastname: Hall
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University , 2333 CC Leiden, The Netherlands.
authors.forename: Eelke B
authors.initials: EB
authors.lastname: Lenselink
authors.affiliation: Schrodinger Inc. , 120 W 45th Street, New York, New York 10036, United States.
authors.forename: Thijs
authors.initials: T
authors.lastname: Beuming
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School , 360 Longwood Avenue, LC-2210, Boston, Massachusetts 02215, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School , 360 Longwood Avenue, LC-2210, Boston, Massachusetts 02215, United States.
authors.forename: James
authors.initials: J
authors.lastname: Bradner
authors.affiliation: Schrodinger Inc. , 120 W 45th Street, New York, New York 10036, United States.
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman
mesh_terms: D000818:Animals; D017076:Computer-Aided Design; D030562:Databases, Protein; D015195:Drug Design; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011506:Proteins