Chapter 15 - Molecular dynamics in predicting the stability of drug-receptor interactions

Abstract

With the growing number of small molecule libraries, computer-aided drug discovery (CADD) now has a profound role in proposing novel molecules to cure ever-increasing diseases and disorders. Molecular simulations are a key step in this process, allowing a closer look into the molecular motions associated with the recognition of biomolecular targets by ligands. This article focuses on the fundamentals of molecular dynamics (MD) and several state-of-the-art concepts in vogue, such as free energy perturbation, umbrella sampling, steered molecule dynamics, MMBAPPL, and MMPBSA/GBSA methods in the context of drug discovery. The study emphasizes how molecular dynamics efficiently helps elucidate the mode of action of drug molecules, identify allosteric or cryptic binding pockets, and decipher mutational effects in the target proteins, not all of which are within the accessible domain of crystallographic experiments. We also present some case studies in which molecular dynamics and free energy simulations, combined with virtual screening and molecular docking, have successfully contributed to novel pharmacological therapeutics. With the growing computer power and development of enhanced sampling techniques, simulation-driven CADD has a prominent role in developing novel drugs and has a bright future.