title: Predictions of Ligand Selectivity from Absolute Binding Free Energy Calculations.
abstract: Binding selectivity is a requirement for the development of a safe drug, and it is a critical property for chemical probes used in preclinical target validation. Engineering selectivity adds considerable complexity to the rational design of new drugs, as it involves the optimization of multiple binding affinities. Computationally, the prediction of binding selectivity is a challenge, and generally applicable methodologies are still not available to the computational and medicinal chemistry communities. Absolute binding free energy calculations based on alchemical pathways provide a rigorous framework for affinity predictions and could thus offer a general approach to the problem. We evaluated the performance of free energy calculations based on molecular dynamics for the prediction of selectivity by estimating the affinity profile of three bromodomain inhibitors across multiple bromodomain families, and by comparing the results to isothermal titration calorimetry data. Two case studies were considered. In the first one, the affinities of two similar ligands for seven bromodomains were calculated and returned excellent agreement with experiment (mean unsigned error of 0.81 kcal/mol and Pearson correlation of 0.75). In this test case, we also show how the preferred binding orientation of a ligand for different proteins can be estimated via free energy calculations. In the second case, the affinities of a broad-spectrum inhibitor for 22 bromodomains were calculated and returned a more modest accuracy (mean unsigned error of 1.76 kcal/mol and Pearson correlation of 0.48); however, the reparametrization of a sulfonamide moiety improved the agreement with experiment.
authors.affiliation: Structural Bioinformatics and Computational Biochemistry, Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, U.K.
authors.forename: Matteo
authors.identifier: 0000-0003-0019-8806
authors.initials: M
authors.lastname: Aldeghi
authors.affiliation: Evotec (U.K.) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
authors.affiliation: Evotec (U.K.) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bodkin
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7BN, U.K.|Institute for Pharmaceutical Chemistry, Goethe University Frankfurt , 60438 Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Structural Bioinformatics and Computational Biochemistry, Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, U.K.
authors.forename: Philip C
authors.identifier: 0000-0001-5100-8836
authors.initials: PC
authors.lastname: Biggin