title: Is ring breaking feasible in relative binding free energy calculations?
abstract: Our interest is relative binding free energy (RBFE) calculations based on molecular simulations. These are promising tools for lead optimization in drug discovery, computing changes in binding free energy due to modifications of a lead compound. However, in the "alchemical" framework for RBFE calculations, some types of mutations have the potential to introduce error into the computed binding free energies. Here we explore the magnitude of this error in several different model binding calculations. We find that some of the calculations involving ring breaking have significant errors, and these errors are especially large in bridged ring systems. Since the error is a function of ligand strain, which is unpredictable in advance, we believe that ring breaking should be avoided when possible.
authors.affiliation: †Department of Pharmaceutical Sciences and Department of Chemistry, University of California, Irvine, 147 Bison Modular, Irvine, California 92697, United States.
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.affiliation: ‡Schrödinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Lingle
authors.initials: L
authors.lastname: Wang
authors.affiliation: †Department of Pharmaceutical Sciences and Department of Chemistry, University of California, Irvine, 147 Bison Modular, Irvine, California 92697, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Mobley
mesh_terms: D005240:Feasibility Studies; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D012709:Serum Albumin; D007052:Ibuprofen
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