Suitability of MMGBSA for the selection of correct ligand binding modes from docking results

Abstract

The estimation of the correct binding mode and affinity of a ligand into a target protein using computational methods is challenging. However, docking can introduce poses from which the correct binding mode could be identified using other methods. Here, we analyzed the reliability of binding energy estimation using the molecular mechanics‐generalized Born surface area (MMGBSA) method without and with energy minimization to identify the likely ligand binding modes within docking results. MMGBSA workflow (a) outperformed docking in recognizing the correct binding modes of androgen receptor ligands and (b) improved the correlation coefficient of computational and experimental results of rescored docking poses to phosphodiesterase 4B. Combined with stability and atomic distance analysis, MMGBSA helped to (c) identify the binding modes and sites of metabolism of cytochrome P450 2A6 substrates. The standard deviation of estimated binding energy within one simulation was lowered by minimization in all three example cases. Minimization improved the identification of the correct binding modes of androgen receptor ligands. Although only three case studies are shown, the results are analogous and indicate that these behaviors could be generalized. Such identified binding modes could be further used, for example, with free energy perturbation methods to understand binding energetics more accurately.

KLF7: a new candidate biomarker and therapeutic target for high-grade serous ovarian cancer

“…However, docking scoring functions employed in high-throughput virtual screening lack accuracy in the approximation of binding affinities of protein-ligand complexes [75]. Hence we filtered the 10 top ranking poses from docking results on the basis of MMG-BSA method, which generally outperforms the scoring functions of docking algorithms [76]. Results obtained have finally allowed the identification of initial hit compounds for further medicinal chemistry optimization to improve their potency and/or selectivity as potential candidates for clinical therapy.…”

Inhibition of human CYP1 enzymes by a classical inhibitor α‐naphthoflavone and a novel inhibitor N‐(3, 5‐dichlorophenyl)cyclopropanecarboxamide: An in vitro and in silico study

“…DG bind was calculated for every simulation snapshot and averaged to obtain DG total . DG total of different ligand binding modes can be used as an estimation of the relative binding affinity to identify the most probable binding modes (Ahinko, Niinivehmas, Jokinen, & Pentikäinen, 2019; Hou, Wang, Li, & Wang, 2011).…”

Construction of 3D Antioxidants with Nucleosides as the Core: Inhibition of DNA Oxidation

“…The reason why the antioxidative effect of 1 (a cytidine as the core bearing four ferulic moieties) is higher than that of pentaerythrityl tetraferulate (pentaerythritol as the core bearing the same number of ferulic acid moieties) encourages us to explore the interaction between an antioxidative molecule with a DNA strand in the manner of molecular docking, during which free energy (Δ G ) is used to be the index for predicting the extent of the intercalation of 1 or pentaerythrityl tetraferulate with a DNA strand . Based on the molecular mechanics-generalized Born surface area, −19.93 kcal/mol of Δ G is generated by pentaerythrityl tetraferulate binding the groove of a DNA strand, but a much lower Δ G (−40.35 kcal/mol) is produced by 1 intercalating with the DtNA groove. Hence, 1 interacts with the DNA groove more tightly than pentaerythrityl tetraferulate.…”