End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design

Abstract

Molecular mechanics Poisson−Boltzmann surface area (MM/PBSA) and molecular mechanics generalized Born surface area (MM/GBSA) are arguably very popular methods for binding free energy prediction since they are more accurate than most scoring functions of molecular docking and less computationally demanding than alchemical free energy methods. MM/PBSA and MM/GBSA have been widely used in biomolecular studies such as protein folding, protein−ligand binding, protein−protein interaction, etc. In this review, methods to adjust the polar solvation energy and to improve the performance of MM/PBSA and MM/GBSA calculations are reviewed and discussed. The latest applications of MM/GBSA and MM/PBSA in drug design are also presented. This review intends to provide readers with guidance for practically applying MM/PBSA and MM/GBSA in drug design and related research fields. CONTENTS 1. Introduction 9478 2. Methodology 9480 3. Assessing the Performance of MM/PBSA and MM/GBSA 9484 4. The Polar Solvation Energy and Entropy Terms in MM/PB(GB)SA Calculations 9485 4.1. The Polar Solvation Energy Term in MM/ PBSA 9485 4.2. The Polar Energy Solvation Term in MM/ GBSA 9486 4.3. Theory, Implementation, and Limitations of the Variable Dielectric Model in MM/GBSA 9487 4.4. Comparison between PB and GB 9488 4.5. Efficient Entropy Calculation Methods To Estimate the Entropy Change upon Ligand Binding 9488 5.

Fast Identification of Possible Drug Treatment of Coronavirus Disease-19 (COVID-19) through Computational Drug Repurposing Study

“…25 Two types of HVS filters were employed: Glide 7 flexible docking followed by MM-PBSA-WSAS. 2,4 Detailed computational methods are described below.…”

Fast Identification of Possible Drug Treatment of Coronavirus Disease -19 (COVID-19) Through Computational Drug Repurposing Study

“…1 Two types of HVS filters were employed: Glide 7 flexible docking followed by MM-PBSA-WSAS. 2,4 Detailed computational methods are described below.…”

“…On the other hand, the molecular mechanical force field (MMFF)-based scoring functions, are physical and more accurate, but much less efficient. With the ever increasing computer power, MMFF-based free energy calculation methods, such as the endpoint MM-PB/GBSA (molecular mechanics-Poisson Boltzmann/ Generalized Born Surface Area) methods 2,3,[8][9][10][11][12][13][14][15][16][17][18][19][20][21] and the alchemical thermodynamic integration (TI) and free energy perturbation (FEP) methods, 22,23 have been extensively applied in structure-based drug discovery projects. Recently we've developed a hierarchical virtual screening (HVS)to balance the efficiency and accuracy and improve the success rate of rational drug design.…”

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“…However, the Δ G pred value is comparable to its analogue Amox (Kong et al, ). The relative rigid molecule structures with fewer flexible bonds in N ‐Des and Amox introduce less entropy loss upon the binding, and the omission of entropy term may lead to the underestimation of binding free energy for this kind of molecules (Chen et al, ; Hou, Wang, Li, & Wang, ; Hou, Wang, Li, & Wang, ; Huang et al, ; Jiang et al, ; Lu, Shen, & Zhang, ; Sun et al, ; Sun, Li, Shen, et al, ; Sun, Li, Tian, Xu, & Hou, ; Wang et al, ; Xu, Sun, Li, Wang, & Hou, ). The non‐polar energy contributions (Δ E vdw + Δ G SA ) are the primary favorable terms in the binding free energy and determine the binding affinities of the studied compounds (Table ).…”