Application of MM-PBSA Methods in Virtual Screening

Abstract

Computer-aided drug design techniques are today largely applied in medicinal chemistry. In particular, receptor-based virtual screening (VS) studies, in which molecular docking represents the gold standard in silico approach, constitute a powerful strategy for identifying novel hit compounds active against the desired target receptor. Nevertheless, the need for improving the ability of docking in discriminating true active ligands from inactive compounds, thus boosting VS hit rates, is still pressing. In this context, the use of binding free energy evaluation approaches can represent a profitable tool for rescoring ligand-protein complexes predicted by docking based on more reliable estimations of ligand-protein binding affinities than those obtained with simple scoring functions. In the present review, we focused our attention on the Molecular Mechanics-Poisson Boltzman Surface Area (MM-PBSA) method for the calculation of binding free energies and its application in VS studies.We provided examples of successful applications of this method in VS campaigns and evaluation studies in which the reliability of this approach has been assessed, thus providing useful guidelines for employing this approach in VS.

Insilico drug repurposing using FDA approved drugs against Membrane protein of SARS-CoV-2

“…The MM-PBSA method was used to estimate the binding affinity of ligands from the last 10 ns simulation trajectories (Table S1). Previous studies confirmed that binding free energy values lower than -30 kJ/mol can be considered for binding, however lower binding free energy values more favorable for interactions 63,64 65 . The binding affinity of the drug Remedesivir was also analyzed with SARS-CoV-RdRp ( Figure S3).…”

Potential protease inhibitors and their combinations to block SARS-CoV-2

“…Of late, MM-PBSA approach is commonly employed to calculate the absolute ΔG bind when long molecular dynamics simulations are done in association with molecular docking studies, particularly when sufficient information about the bioactive conformation of the protein -ligand complex are not available. Moreover, this approach can be used to screen out active compounds and its structure -activity relationship, virtual screening and improve the results of molecular docking (Poli et al., 2020 ). In addition to the docking parameters, thermodynamic parameters of molecular dynamics conformations have also been analysed in the present study.…”

Resources and computational strategies to advance small molecule SARS-CoV-2 discovery: Lessons from the pandemic and preparing for future health crises

“…The compound collections can be, like in LBVS studies, approved, investigational or experimental molecules [203] , purchasable compounds and virtual compounds [204] , covalent binders [130] , [205] or small fragments [206] . Different types of scoring functions can then be used to select the molecules for experimental assays [155] , [157] , [160] , [207] , [208] , [209] , [210] , [211] . LBVS and SBVS can be combined if the right data are available [134] .…”