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Improving virtual screening results with MM/GBSA and MM/PBSA rescoring

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Abstract

Virtual screening (VS) based on molecular docking is one of the most useful methods in computer-aided drug design. By allowing to identify computationally putative ligands binding to the proteins of interest, VS dramatically reduces the time and expense of the development of novel therapeutics. Among the limitations of the VS approaches is the low accuracy of scoring functions implemented in docking methods for assessing binding affinity. Many such scoring functions are developed for rapid, high-throughput evaluation of binding energy of multiple conformations generated by a searching algorithm. The methods for more rigorous calculation of binding affinity calculation are generally time-consuming. Even so, in many studies more accurate methods were used for rescoring of the final poses and false-positive hits evaluation. We performed VS for three benchmark sets and used energy minimization with MM/PB(GB)SA methods (molecular mechanics energies combined with the Poisson–Boltzmann or generalized Born and surface area) to rescore binding affinities. The comparison of the area under the curve (AUC), enrichment factor (EF), and Boltzmann-enhanced discrimination of receiver operating characteristics (BEDROC) showed essential improvements in the binding energy prediction after the rescoring. Finally, we provide a program for minimization and rescoring VS results based on freely available AmberTools. The code requires just the final binding poses of the ligand as the input and can be used with any docking program.

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Code availability

https://github.com/sahakyanhk/iPBSA.

Abbreviations

AM1-BCC:

Austin Model 1-bond charge corrections

AUC:

Area under the curve

BEDROC:

Boltzmann-enhanced discrimination of receiver operating characteristics

EF:

Enrichment factor

FABP4:

Fatty acid binding protein 4

FEP:

Free energy perturbation

FPR:

False-positive rates

GAFF:

General Amber Force Field

KITH:

Thymidine kinase

MM/GBSA:

Molecular Mechanics generalized Born Surface Area

MM/PBSA:

Molecular Mechanics Poisson-Boltzmann Surface Area

PUR2:

Phosphoribosylglycinamide formyltransferase

ROC:

Receiver operating characteristics curve

TI:

Thermodynamic integration

TPR:

True-positive rates

VS:

Virtual screening

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Acknowledgements

We are grateful to Arcady Mushegian and Irina Sorokina for helpful discussion and comments. We also thank Joint Institute for Nuclear Research (Dubna, Russia) for provided HPC resources.

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Authors and Affiliations

  1. Institute of Molecular Biology, National Academy of Sciences of the Republic of Armenia, 0014, Yerevan, Armenia

    Harutyun Sahakyan

  2. Denovo Sciences, 0033, Yerevan, Armenia

    Harutyun Sahakyan

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Correspondence to Harutyun Sahakyan.

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Sahakyan, H. Improving virtual screening results with MM/GBSA and MM/PBSA rescoring. J Comput Aided Mol Des 35, 731–736 (2021). https://doi.org/10.1007/s10822-021-00389-3

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  • DOI: https://doi.org/10.1007/s10822-021-00389-3

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