Free Energy-Based Methods to Understand Drug Resistance Mutations

Abstract

In this chapter, we present an overview of various computational methods, particularly, those that are used to compute the free energy of binding to understand target site mutations that will enable us to foresee mutations that could significantly affect drug binding. We begin by looking at the driving forces that lead to drug resistance and throw some light on the various mechanisms by which drugs can be rendered ineffective. Next, we studied molecular dynamic simulations and its use to understand the thermodynamics of protein–ligand interactions. Building on these fundamentals, we discuss various methods that are available to compute the free energy binding, their mathematical formulations, the practical aspects of each these methods and finally their use in understanding drug resistance.