QM / MM for Structure‐Based Drug Design: Techniques and Applications

Combined quantum mechanics/molecular mechanics (QM/MM) allow the inclusion of electronic effects (polarization, bonding changes) while efficiently modeling large systems, such as drug targets. Alongside some promising applications for the evaluation of non-covalent drug binding, QM/MM methods are particularly relevant for providing insights into covalent drug design. Through QM/MM, chemical reactions in biomolecules, e.g. between drugs and their targets, can be characterized in detail. Hence, insight into covalent drug targets can be obtained, the reactivity of so-called warheads evaluated, and drug resistance better understood, including how such resistance could be combated. Here, we first briefly outline the methodological aspects of QM/MM modeling. Then, recent applications of QM/MM methods related to covalent drug design will be discussed, highlighting applications to several key drug target families: tyrosine kinases, β-lactamases, and viral proteases from SARS-CoV-2.