Target-Related Applications of First Principles Quantum Chemical Methods in Drug Design

In this article, we review some recent (covering approximately the last four years) applications of QM-based methods in drug design, exclusively focusing on target-based studies carried out on pharmacologically relevant biological systems (enzymes, receptors, ion channels). In particular, we present some case studies laying down the perspectives about a wider usage of QM-based methods in computational medicinal chemistry, and about the exploitation of QM results in the rational drug design. The selected case studies are intended to show the suitability of QM methods to describe electronic and dynamic features of ligand/target interactions and enzymatic reactions, and allow us to discuss the relevance for drug-oriented studies of atomistic situations that can be properly described only taking into account electronic and nuclear quantum effects, such as the geometries of metal carrying active sites, the quantum hydrogen tunneling, and the cation-pi interaction. Even if it is clearly out of the scope of the paper to provide a thorough account of the theory at the basis of first principles QM methods, we also provide a succinct introduction to the main concepts underlying QM, DFT, and QM/MM approaches.