Free-energy calculations from theory to drug discovery

Professor William L. Jorgensen

Department of Chemistry, Yale University, New Haven, CT 06520-8107

Free-energy calculations have had a revolutionary effect on computational chemistry. In conjunction with molecular dynamics and Monte Carlo simulations, they have enabled the calculation of free energy changes for wide-ranging phenomena including fundamental solution thermodynamics, activation barriers for reactions in solution, host-guest binding, and drug lead optimization. An overview of our FEP efforts beginning with the ethane to methanol calculation in 1985 and leading to recent discoveries of extraordinarily potent inhibitors of the main protease of SARS-CoV-2 will be presented.

Figure 1. Rendering from a 1.8-Å crystal structure for a complex with the main protease of SARS-CoV-2
(PDB ID 7L11). Carbon atoms of the ligand are in yellow.

Recording:

References

Computer-Aided Discovery of Anti-HIV Agents. Jorgensen, W. L. Bioorg. Med. Chem. 2016, 24, 4768-4788.

Robust FEP Protocols for Creating Molecules in Solution. Cabeza de Vaca, I.; Zarzuela, R.; Tirado-Rives, J.; Jorgensen, W. L. J. Chem. Theory Comput. 2019, 15, 2734-2742.

Absolute Free Energy of Binding Calculations for Macrophage Migration Inhibitory Factor in Complex with a Drug-like Inhibitor. Qian, Y.; Cabeza de Vaca, I.; Vilseck, J. Z.; Cole, D. J.; Tirado-Rives, J.; Jorgensen, W. L. J. Phys. Chem. B 2019, 123, 8675-8685.

Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2. Ghahremanpour, M.; Tirado-Rives, J.; Deshmukh, M.; Ippolito, J. A.; Zhang, C.-H.;Cabeza de Vaca, I.; Liosi, M.-E.; Anderson, K. S.; Jorgensen, W. L. ACS Med. Chem. Lett. 2020, 11, 2626-2533.

Potent non-covalent inhibitors of the main protease of SARS-CoV-2 from molecular sculpting of the drug parampanel guided by free-energy perturbation calculations. Zhang, C.-H.; Stone, E. A.; Deshmukh, M.; Ippolito, J. A.; … Anderson, K. S.; Jorgensen, W. L. ACS Central Sci. 2021, 00, 0000-0000.