Accurate prediction of binding affinities has long been a central goal of computational chemistry, yet remains elusive, with the required accuracy for use in a drug-discovery context that has not been consistently achieved for drug-like molecules. However, thanks to recent advances in theory and computing, predictions of binding affinities using physics-based simulations are gaining popularity. In particular, binding free energy estimates based on molecular dynamics and alchemical pathways have been shown to be a rigorous approach for the affinity prediction problem and hold the promise to be able to guide lead optimization. Whilst relative calculations have started being employed in a drug-discovery context, absolute calculations still lack validation against drug-like molecules and real therapeutic targets.<br/><br/>We performed absolute free energy calculations based on an alchemical thermodynamic cycle for a set of diverse inhibitors binding to bromodomain-containing protein 4 (BRD4) and show that accurate results can be obtained, when starting from either x-ray structures or docked ligand poses. Furthermore, we assessed the ability of the calculations to reproduce the affinity profile of a broad-spectrum inhibitor across multiple bromodomain families. Bromodomains are epigenetic mark readers that recognize acetylation motifs on histones and regulate gene transcription, and are now an established target in oncology. The results achieved by the estimates offer the exciting prospect that the binding affinity of drug-like molecules may be accurately predicted for pharmacologically relevant targets.

Absolute free energy of binding for drug molecules: Application to bromodomains

251st National Meeting (2016)

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