Introduction: Computational chemistry has become an established and valuable component in structure-based drug design. However the chemical complexity of many ligands and active sites challenges the accuracy of the empirical potentials commonly used to describe these systems. Consequently, there is a growing interest in utilizing electronic structure methods for addressing problems in protein–ligand recognition.

Areas covered: In this review, the authors discuss recent progress in the development and application of quantum chemical approaches to modeling protein–ligand interactions. The authors specifically consider the development of quantum mechanics (QM) approaches for studying large molecular systems pertinent to biology, focusing on protein–ligand docking, protein–ligand binding affinities and ligand strain on binding.

Expert opinion: Although computation of binding energies remains a challenging and evolving area, current QM methods can underpin improved docking approaches and offer detailed insights into ligand strain and into the nature and relative strengths of complex active site interactions. The authors envisage that QM will become an increasingly routine and valued tool of the computational medicinal chemist.