Molecular Dynamics Simulation Techniques as Tools in Drug Discovery and Pharmacology: A Focus on Allosteric Drugs

Allosteric drugs are ligands that when bound to an allosteric site modify the conformational state of the pharmacological target, leading then to a modification of functional response upon binding of the endogenous ligand. Pharmacological targets are defined as biological entities, to which a ligand/drug binds and leads to a functional effect. Pharmacological targets can be proteins or nucleic acids. Computational approaches such as molecular dynamics (MD) sped up discovery and identification of allosteric binding sites and allosteric ligands. Classical all-atom and hybrid classical/quantum MD simulations can be generalized as simulation techniques aimed at analysis of atoms and molecular motion. Main limitations of MD simulations are related to high computational costs, that in turn limit the conformational sampling of biological systems. Indeed, other techniques have been developed to overcome limitations of MD, such as enhanced sampling MD simulations. In this chapter, classical MD and enhanced sampling MD simulations will be described, along with their application to drug discovery, with a focus on allosteric drugs.