Journal
CHEMICAL SCIENCE
Volume 7, Issue 1, Pages 207-218Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5sc02678d
Keywords
-
Categories
Funding
- EPSRC
- Evotec
- SGC [1097737]
- Bayer
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Canadian Institutes for Health Research
- Genome Canada
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Takeda
- Wellcome Trust [092809/ZZ/1010/ZZ]
- AbbVie
- EPSRC [EP/L000253/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/L000253/1, 1233347] Funding Source: researchfish
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available