An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge

Abstract

Molecular Dynamics (MD) has become increasingly popular due to the development of hardware and software solutions and improvement in algorithms, that allowed researchers to scale up calculations in order to speed up them. MD simulations are usually used to address protein folding issues or protein-ligand complex stability through energy profile analysis over time. In recent years, the development of new tools able to deeply explore Potential Energy Surface (PES) allowed researchers to focus on the dynamic nature of binding recognition process and binding-induced protein conformational change. Moreover, modern approaches have demonstrated to be effective and reliable in calculating some kinetic and thermodynamic parameters behind the host-guest recognition process. Starting from all of these considerations, several efforts have been made in order to integrate MD within the virtual screening process in drug discovery. Knowledge retrieved from MD can be, in fact, exploited as a starting point to build pharmacophores or docking constraints in the early stage of the screening campaign as well as to define key features, in order to unravel hidden binding modes and help the optimisation of the molecular structure of a lead compound. Based on these outcomes, researchers are nowadays using MD as an invaluable tool to discover and target previously considered undruggable binding sites, including protein-protein interactions and allosteric sites on protein surface. As a matter of fact, the use of MD has been recognised as vital in the discovery of selective protein-protein interaction modulators. The use of a dynamic overview on how the host-guest recognition occurs and of the relative conformational modifications induced, allow researchers to optimise small molecules and small peptides capable to tightly interact within the cleft between the two proteins. In this review we point to present the most recent applications of MD as integrated tool to be used in the rational design of small molecules or small peptides able to modulate undruggable targets, such as allosteric sites and protein-protein interactions.