Metal–ligand interactions in drug design

The fast-growing body of experimental data on metalloenzymes and organometallic compounds is fostering the exploitation of metal–ligand interactions for the design of new drugs. Atomistic understanding of the metal–ligand interactions will help us identify potent metalloenzyme inhibitors and metallodrugs. Static docking calculations have proved effective in identifying hit compounds that target metalloproteins. However, the flexibility, dynamics and electronic structure of metal-centred complexes pose difficult challenges for shaping metal–ligand interactions in structure-based drug design. In this respect, once-prohibitive quantum mechanics-based strategies and extensive molecular simulations are rapidly becoming practical approaches for fast-paced drug discovery. These methods account for ligand exchange and structural flexibility at metal-centred complexes and provide good estimates of the thermodynamics and kinetics of metal-aided drug binding. This Perspective examines the successes, limitations and new avenues for modelling metalloenzyme inhibitors and metallodrugs to further explore and expand the unconventional chemical space of these distinctive drugs