Quantum Mechanical Calculations in Medicinal Chemistry: Relevant Method or a Quantum Leap Too Far?

Abstract

Quantum mechanical calculations are a very important and unique computational tool for answering complex questions related to medicinal chemistry and drug design that cannot be addressed by any other computational method. Although quantum mechanical calculations are now applied widely in medicinal chemistry and drug design, they do not have as high a profile, visibility, and recognition in the computational chemistry or the medicinal chemistry community as other computational techniques, like for example quantitative structure–activity relationships (QSAR), virtual screening, chemoinformatics, library design, or protein homology modeling. Major advances in computer power over the last 25 years have enabled computational chemists to apply successfully these types of calculations for example to determine accurately molecular structures and properties for use in a wide variety of QSAR studies that range from predicting binding affinities to absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. In addition, reaction mechanisms and energies in organic as well as enzymatic reactions have been investigated extensively as well as structure-based drug design approaches that treat part or even all of the protein–ligand complex quantum mechanically. This chapter outlines the usefulness of quantum mechanical calculations for applications in medicinal chemistry and drug design by highlighting recent examples for use cases of these methods to problems relevant in the design of small molecule pharmacological therapies.