Rigorous Free Energy Simulations in Virtual Screening.

Journal of Chemical Information and Modeling
Zoe CourniaWoody Sherman

Abstract

Virtual high throughput screening (vHTS) in drug discovery is a powerful approach to identify hits: when applied successfully, it can be much faster and cheaper than experimental high-throughput screening approaches. However, mainstream vHTS tools have significant limitations: ligand-based methods depend on knowledge of existing chemical matter, while structure-based tools such as docking involve significant approximations that limit their accuracy. Recent advances in scientific methods coupled with dramatic speedups in computational processing with GPUs make this an opportune time to consider the role of more rigorous methods that could improve the predictive power of vHTS workflows. In this Perspective, we assert that alchemical binding free energy methods using all-atom molecular dynamics simulations have matured to the point where they can be applied in virtual screening campaigns as a final scoring stage to prioritize the top molecules for experimental testing. Specifically, we propose that alchemical absolute binding free energy (ABFE) calculations offer the most direct and computationally efficient approach within a rigorous statistical thermodynamic framework for computing binding energies of diverse molecules, as is re...Continue Reading

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Citations

Jan 30, 2021·Journal of Chemical Information and Modeling·Benjamin RiesSereina Riniker
Oct 15, 2020·Proceedings of the National Academy of Sciences of the United States of America·Zhe LiHai-Bin Luo
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Sep 14, 2021·Journal of Chemical Theory and Computation·Si ZhangVincent A Voelz
Sep 15, 2021·Journal of Chemical Information and Modeling·Stamatia ZavitsanouZoe Cournia
Sep 23, 2021·Journal of Chemical Theory and Computation·Yudong QiuLee-Ping Wang
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