QM Implementation in Drug Design: Does It Really Help?

Jinfeng Liu, Xiao He

Methods in molecular biology (Clifton, N.J.) 2020

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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?