Accurate prediction of the protein-ligand binding affinity is one of the major tasks in computer-aided drug design (CADD) projects, especially in the stage of lead-optimization. In principle the alchemical free energy (AFE) methods can fulfill this task, but a lot of hurdles prevent them from being routinely applied in daily drug design projects, such as the demanding computer resources, slow computing processes, unavailable or inaccurate force field parameters, etc. A commercial software package such as the Schrodinger/FEP+ can greatly alleviate the difficulties and accelerate the routine usage of AFE methods, but the software is costly for both  academic and industrial labs. In this study, we have exploited practical protocols of adopting the newly-developed GPU TI modules and other tools in AMBER software package, combined with the ff14SB/GAFF1.8 force fields, to conduct efficient and accurate AFE calculations on protein-ligand binding free energies. We have tested 133 protein-ligand complexes in total for 4 protein targets (BACE, CDK2, MCL1, and PTP1B), and obtained mean unsigned errors (MUEs) and root mean square errors (RMSEs) lower than not only those from Schrodinger FEP+, but also the threshold criterion (1 kcal/mol) for effectively guiding  experimental work in drug lead optimization, and the needed wall time is short enough for practical application. Considering AMBER force fields are free to public and AMBER package charges relatively very low prices for academic and industrial labs, our verified protocol provides a practical solution for routine AFE calculations in real drug-design projects.

Practical protocols for calculations of protein-ligand binding free energies in daily drug-design projects using AMBER GPU-TI with ff14SB/GAFF

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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