The Increasing Role of QM/MM in Drug Discovery

Since its first appearance in 1976, the quantum mechanics/molecular mechanics (QM/MM) approach has mostly been used to study the chemical reactions of enzymes, which are frequently the target of drug discovery programs. In principle, a detailed understanding of the enzymatic mechanism should help researchers to design a potent enzyme inhibitor or new drug. However, QM/MM has not yet had a widespread impact on structure-based drug design. This is mostly due to its high computational cost. We expect this to change with the recent and extraordinary increases in computational power, and with the availability of more efficient algorithms for QM/MM calculations. Here, we report on some representative examples of QM/MM studies, including our own research, of pharmaceutically relevant enzymes, such as ribonuclease H and fatty acid amide hydrolase (FAAH). We aim to show how QM/MM has traditionally been used to study enzymatic catalysis. In this regard, we discuss its potential to become a routinely used drug design tool. To support this, we also discuss selected computational studies where QM/MM insights have been helpful in improving the potency of covalent inhibitors of FAAH.