QM Implementation in Drug Design: Does It Really Help?

Computational chemistry allows one to characterize the structure, dynamics, and energetics of protein–ligand interactions, which makes it a valuable tool in drug discovery in both academic research and pharmaceutical industry. Molecular mechanics (MM)-based approaches are widely utilized to assist the discovery of new drug candidates. However, the complexity of protein–ligand interactions challenges the accuracy and efficiency of the commonly used empirical methods. Aiming to provide better accuracy in the description of protein–ligand interactions, quantum mechanics (QM)-based approaches are becoming increasingly explored. In principle, QM calculation includes all contributions to the energy, accounting for terms usually missing in empirical force fields, and provides a greater degree of transferability. The usefulness of QM in drug design cannot be overemphasized. In this chapter, we present recent developments and applications of fragment-based QM method in studying the protein–ligand and protein–protein interactions. We critically discuss the performance of the fragment-based QM method at different ab initio levels while trying to answer a critical question: do QM-based methods really help in drug design?.