Fast and accurate predictions of binding free energies using MM‐PBSA and MM‐GBSA

By Giulio Rastelli, A. D. Rio, G. Degliesposti, M. Sgobba. Journal of Computational Chemistry, 2009

754 citations recorded by the source corpus.

In the drug discovery process, accurate methods of computing the affinity of small molecules with a biological target are strongly needed. This is particularly true for molecular docking and virtual screening methods, which use approximated scoring functions and struggle in estimating binding energies in correlation with experimental values. Among the various methods, MM‐PBSA and MM‐GBSA are emerging as useful and effective approaches. Although these methods are typically applied to large collections of equilibrated structures of protein‐ligand complexes sampled during molecular dynamics in water, the possibility to reliably estimate ligand affinity using a single energy‐minimized structure and implicit solvation models has not been explored in sufficient detail. Herein, we thoroughly investigate this hypothesis by comparing different methods for the generation of protein‐ligand complexes and diverse methods for free energy prediction for their ability to correlate with experimental values. The methods were tested on a series of structurally diverse inhibitors of Plasmodium falciparum DHFR with known binding mode and measured affinities. The results showed that correlations between MM‐PBSA or MM‐GBSA binding free energies with experimental affinities were in most cases excellent. Importantly, we found that correlations obtained with the use of a single protein‐ligand minimized structure and with implicit solvation models were similar to those obtained after averaging over multiple MD snapshots with explicit water molecules, with consequent save of computing time without loss of accuracy. When applied to a virtual screening experiment, such an approach proved to discriminate between true binders and decoy molecules and yielded significantly better enrichment curves. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010

Subfields: Computational Theory and Mathematics, Molecular Biology, Organic Chemistry

View Paper: https://www.semanticscholar.org/paper/b611bb649b3d3983638602afa816a35c266fdc59

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In Computational Theory and Mathematics

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In Organic Chemistry

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Citations in the corpus

• Molecular dynamics simulations and novel drug discovery (2018, methodology): “MD simulations combined with binding free energy calculations have also been shown to be a good strategy to improve the enrichment factor of virtual screening because it can improve the accuracy of binding ability prediction between ligands and the target [16,17].”
• The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities (2015, background): “It has been argued that more time can be saved by performing the minimizations in a GB continuum solvent [32].”
• In silico methods and tools for drug discovery (2021, background): “These methods have successfully reproduced experimental results and can thus improve molecular docking results [193].”