Free energy perturbation calculations of tetrahydroquinolines complexed to the first bromodomain of BRD4

Silva, Arnaldo F.; Guest, Ellen E.; Falcone, Bruno N.; Pickett, Stephen D.; Rogers, David M.; Hirst, Jonathan D.

Abstract

Alchemical free energy perturbation (FEP) theory is widely used nowadays to calculate protein–ligand binding energies, often in support of drug discovery endeavours. We assess the accuracy and sensitivity of absolute FEP binding energies with respect to the CHARMM/CGenFF and the AMBER/GAFF force field parameterisations for a set of tetrahydroquinoline inhibitors of the first bromodomain of BRD4, a target of keen interest for the development of anti-cancer drugs. We find that AMBER/GAFF is better able than CHARMM/CGenFF to cover the range of and to distinguish between the relative binding energies of the 16 ligands.

Citation

Silva, A. F., Guest, E. E., Falcone, B. N., Pickett, S. D., Rogers, D. M., & Hirst, J. D. (2022). Free energy perturbation calculations of tetrahydroquinolines complexed to the first bromodomain of BRD4. Molecular Physics, https://doi.org/10.1080/00268976.2022.2124201

• Journal Article Type: Article
• Acceptance Date: Sep 6, 2022
• Online Publication Date: Oct 12, 2022
• Publication Date: Oct 12, 2022
• Deposit Date: Sep 26, 2022
• Publicly Available Date: Oct 13, 2023
• Journal: Molecular Physics
• Print ISSN: 0026-8976
• Electronic ISSN: 1362-3028
• Publisher: Taylor and Francis
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1080/00268976.2022.2124201
• Keywords: Physical and Theoretical Chemistry; Condensed Matter Physics; Molecular Biology; Biophysics
• Public URL: https://nottingham-repository.worktribe.com/output/11744230
• Publisher URL: https://www.tandfonline.com/doi/full/10.1080/00268976.2022.2124201