Estimation of the Binding Free Energy by Linear Interaction Energy Models

O.      Nicolotti; M.      Convertino; F.      Leonetti; M.      Catto; S.      Cellamare; A.      Carotti

doi:10.2174/138955712800493843

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.

Keywords: Binding free energy, linear interaction energy, extended linear response, molecular mechanics generalized born surface area, linear interaction energy in continuum electrostatics, macromolecules, LIE, FEP, COX-2 inhibitors, SGB-LIE, in vacuo