title: Accurate calculation of the absolute free energy of binding for drug molecules.
abstract: Accurate prediction of binding affinities has been a central goal of computational chemistry for decades, yet remains elusive. Despite good progress, the required accuracy for use in a drug-discovery context has not been consistently achieved for drug-like molecules. Here, we perform absolute free energy calculations based on a thermodynamic cycle for a set of diverse inhibitors binding to bromodomain-containing protein 4 (BRD4) and demonstrate that a mean absolute error of 0.6 kcal mol-1can be achieved. We also show a similar level of accuracy (1.0 kcal mol-1) can be achieved in pseudo prospective approach. Bromodomains are epigenetic mark readers that recognize acetylation motifs and regulate gene transcription, and are currently being investigated as therapeutic targets for cancer and inflammation. The unprecedented accuracy offers the exciting prospect that the binding free energy of drug-like compounds can be predicted for pharmacologically relevant targets.
authors.affiliation: Structural Bioinformatics and Computational Biochemistry , Department of Biochemistry , University of Oxford , South Parks Road , Oxford , OX1 3QU , UK . Email: philip.biggin@bioch.ox.ac.uk ; ; Tel: +44 (0)1865 613305.
authors.forename: Matteo
authors.initials: M
authors.lastname: Aldeghi
authors.affiliation: Evotec (U.K.) Ltd , 114 Innovation Drive, Milton Park , Abingdon , Oxfordshire OX14 4RZ , UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
authors.affiliation: Evotec (U.K.) Ltd , 114 Innovation Drive, Milton Park , Abingdon , Oxfordshire OX14 4RZ , UK.
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 , UK ; Target Discovery Institute , Nuffield Department of Clinical Medicine , University of Oxford , Roosevelt Drive , Oxford OX3 7BN , UK.
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 , UK . Email: philip.biggin@bioch.ox.ac.uk ; ; Tel: +44 (0)1865 613305.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Biggin