Bridging quantum mechanics and structure-based drug design

Abstract

The last decade has seen great advances in the use of quantum mechanics (QM) to solve biological problems of pharmaceutical relevance. For instance, enzymatic catalysis is often investigated by means of the so-called QM/MM approach, which uses QM and molecular mechanics (MM) methods to determine the (free) energy landscape of the enzymatic reaction mechanism. Here, I will discuss a few representative examples of QM and QM/MM studies of important metalloenzymes of pharmaceutical interest (i.e. metallophosphatases and metallo-beta-lactamases). This review article aims to show how QM-based methods can be used to elucidate ligand-receptor interactions. The challenge is then to exploit this knowledge for the structure-based design of new and potent inhibitors, such as transition state (TS) analogues that resemble the structure and physicochemical properties of the enzymatic TS. Given the results and potential expressed to date by QM-based methods in studying biological problems, the application of QM in structure-based drug design will likely increase, making of these once-prohibitive computations a routinely used tool for drug design.