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Enhancing Hit Discovery in Virtual Screening through Absolute Protein–Ligand Binding Free-Energy Calculations

Cite this: J. Chem. Inf. Model. 2023, 63, 10, 3171–3185
Publication Date (Web):May 11, 2023
https://doi.org/10.1021/acs.jcim.3c00013
Copyright © 2023 American Chemical Society

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    Abstract

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    In the hit identification stage of drug discovery, a diverse chemical space needs to be explored to identify initial hits. Contrary to empirical scoring functions, absolute protein–ligand binding free-energy perturbation (ABFEP) provides a theoretically more rigorous and accurate description of protein–ligand binding thermodynamics and could, in principle, greatly improve the hit rates in virtual screening. In this work, we describe an implementation of an accurate and reliable ABFEP method in FEP+. We validated the ABFEP method on eight congeneric compound series binding to eight protein receptors including both neutral and charged ligands. For ligands with net charges, the alchemical ion approach is adopted to avoid artifacts in electrostatic potential energy calculations. The calculated binding free energies correlate with experimental results with a weighted average of R2 = 0.55 for the entire dataset. We also observe an overall root-mean-square error (RMSE) of 1.1 kcal/mol after shifting the zero-point of the simulation data to match the average experimental values. Through ABFEP calculations using apo versus holo protein structures, we demonstrated that the protein conformational and protonation state changes between the apo and holo proteins are the main physical factors contributing to the protein reorganization free energy manifested by the overestimation of raw ABFEP calculated binding free energies using the holo structures of the proteins. Furthermore, we performed ABFEP calculations in three virtual screening applications for hit enrichment. ABFEP greatly improves the hit rates as compared to docking scores or other methods like metadynamics. The good performance of ABFEP in rank ordering compounds demonstrated in this work confirms it as a useful tool to improve the hit rates in virtual screening, thus facilitating hit discovery.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jcim.3c00013.

    • Detailed methods for calculation of free-energy correction due to protonation state changes; detailed screening procedure of Galapagos evaluation; note regarding WScore; Comparison of experimental IC50 and Ki for JNK1; AUC of the ROC curves for JAK2; ranking of hits identified in the virtual screening against the Galapagos target; results of ABFEP repeats 2 and 3 for the congeneric compound series; salt bridge and hydrogen bond interactions between ligand and protein for PTP1B; thermodynamic cycle for the coupling between BACE1 Asp titration and ligand binding; comparison of hit enrichment for JAK2 using different methods; comparison of WScore results on the Galapagos purchase list (PDF)

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    This article is cited by 16 publications.

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    14. Mohammad M. Ghahremanpour, Anastasia Saar, Julian Tirado-Rives, William L. Jorgensen. Computation of Absolute Binding Free Energies for Noncovalent Inhibitors with SARS-CoV-2 Main Protease. Journal of Chemical Information and Modeling 2023, 63 (16) , 5309-5318. https://doi.org/10.1021/acs.jcim.3c00874
    15. Finlay Clark, Graeme Robb, Daniel J. Cole, Julien Michel. Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations. Journal of Chemical Theory and Computation 2023, 19 (12) , 3686-3704. https://doi.org/10.1021/acs.jctc.3c00139
    16. Mikolai Fajer, Ken Borrelli, Robert Abel, Lingle Wang. Quantitatively Accounting for Protein Reorganization in Computer-Aided Drug Design. Journal of Chemical Theory and Computation 2023, 19 (11) , 3080-3090. https://doi.org/10.1021/acs.jctc.3c00009

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