An accurate free energy estimator: based on MM/PBSA combined with interaction entropy for protein–ligand binding affinity

Abstract

Modifying the energy term and considering the entropic contribution by IE method significantly improve the accuracy of predicted binding free energy in MM/PBSA method.

The FDA-approved drug cobicistat synergizes with remdesivir to inhibit SARS-CoV-2 replication

“…A lack of binding stability of the ligands within the active site of 3CL pro might explain the discrepancy between the FRET experimental results and the previous in-silico predictions indicating cobicistat as a 3CL pro inhibitor. In particular, when assessment of conformational entropy was included in the molecular dynamics analysis(48), the binding of cobicistat tended to be less stable than that of other ligands (Supplementary Table 3; Supplementary Movie 1) and the predicted binding energies to 3CL pro of the examined ligands reflected more closely the EC50 values calculated by FRET (Supplementary Figure 3; Supplementary Table 3).…”

“…The copyright holder for this preprint this version posted March 9, 2021. ; https://doi.org/10.1101/2021.03.09.434219 doi: bioRxiv preprint as a 3CLpro inhibitor. In particular, when assessment of conformational entropy was included in the molecular dynamics analysis (48), the binding of cobicistat tended to be less stable than that of other ligands (Supplementary Table 3; Supplementary Movie 1) and the predicted binding energies to 3CLpro of the examined ligands reflected more closely the EC50 values calculated by FRET ( Supplementary Figure 3; Supplementary Table 3). We thus proceeded to analyze the possible impact of cobicistat on other key viral proteins.…”

“…Other parameters were left at their default values. The entropic contribution was estimated using a previously described method of calculation of interaction entropy (48,79).…”

Protein–ligand free energies of binding from full-protein DFT calculations: convergence and choice of exchange–correlation functional

“…57 A variety of improvements to the original formulation by Kollman et al 49 have also been suggested. Duan et al 58 have proposed an alternative method, called interaction entropy, of estimating the entropy correction term in MM-PBSA. More involved definitions of the solvent accessible surface area (SASA) like the weighted-SASA 54 approach have also been developed as well as volume based estimates of the cavitation energy in the non-polar solvation term.…”

Potential of pyrroquinazoline alkaloids fromAdhatoda vasicaNees. as inhibitors of 5-LOX – a computational and anin-vitrostudy

“…we substituted the van der Waals, electrostatic, polar solvation, non-polar solvation energies derived from the MM-PBSA module and the interaction entropy obtained in the Equation 7. Equation 7is an optimal estimator derived from a study (Huang et al, 2020) that achieved high correlation between experimental and theoretical binding energy values, using Internal entropy and energy terms obtained with the MM-PBSA module.…”