Issue 1, 2016

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−1 can 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.

Graphical abstract: Accurate calculation of the absolute free energy of binding for drug molecules

Supplementary files

Article information

Article type
Edge Article
Submitted
23 jul 2015
Accepted
24 sep 2015
First published
25 sep 2015
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2016,7, 207-218

Author version available

Accurate calculation of the absolute free energy of binding for drug molecules

M. Aldeghi, A. Heifetz, M. J. Bodkin, S. Knapp and P. C. Biggin, Chem. Sci., 2016, 7, 207 DOI: 10.1039/C5SC02678D

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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