Estimation of the Binding Free Energy by Linear Interaction Energy Models

Abstract

Since Hansch's extra thermodynamic multi-parameter approach, originally coined as Linear Free Energy Relationship, great efforts in medicinal chemistry have been made to properly estimate the binding free energy. Despite the often small amount, its value is however very critical in determining a successful binding. As a result, its correct estimation may provide a guide for a prospective rational drug design. The calculation of the absolute binding free energies is however a very challenging task as it requires a rigorous treatment of a number of physical terms that are both very time demanding and to some extent not immediately interpretable. In view of this, the introduction of some numerical approximations has permitted to develop the so called Linear Interaction Energy method that, at present, constitutes the best compromise among accuracy, speed of computation and easy interpretation. The initially developed Linear Interaction Energy method was subsequently revisited and several important improvements have been made. Significant examples are the Extended Linear Response, the surface generalized Born LIE, the molecular mechanics generalized Born surface area, the linear interaction energy in continuum electrostatics as well as its quantum mechanics variant. Principles and selected applications of these methods will be herein reviewed.

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

“…The most well known end-point free energy methods are molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) and molecular mechanics generalized Born surface area (MM/GBSA), developed by Kollman et al, − which achieve a good balance between computational efficiency and accuracy and thus are the focus of this review. Since the PB solution ,, is computationally time-consuming, a set of more efficient approximation methods based on the GB model − have been developed and have attracted more and more attention. − Another popular method with intermediate performance is linear interaction energy (LIE) ,− , whose computational efficiency is second only to that of the scoring function, but we will not discuss it in this review. MM/PBSA and MM/GBSA have been widely used to evaluate docking poses, determine structural stability, and predict binding affinities and hotspots.…”

Development and Evaluation of MM/GBSA Based on a Variable Dielectric GB Model for Predicting Protein–Ligand Binding Affinities

“…However, the above two sets of methods cannot achieve a good balance between prediction accuracy and computational efficiency. In the past decade, the end-point methods, − especially the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) and molecular mechanics generalized Born surface area (MM/GBSA) approaches, have been attracting more and more attentions. With the rapid development of computation hardware, the end-point methods have been extensively utilized in lead optimization and even large-scale virtual screening. − Moreover, molecular dynamics (MD) simulations with the explicit solvent model are generally employed to generate structure ensembles for binding free energy predictions; , albeit, minimizations yield as good or even better predictions as MD simulations in some cases. ,− …”