Molecular simulation methods in drug discovery: a prospective outlook

Over the last decades, molecular simulations have spread through the drug discovery arena. This trend is expected to continue in the foreseeable future thanks to increased performance and the positive impact they can exert on productivity. In this article we highlight three aspects of molecular modelling for which we expect significant improvements over the next 25 years. Increased computational resources, faster algorithms and novel methods to sample rare events will provide a better handle on target flexibility and its relation with ligand binding. More accurate target druggability predictions will improve the success, but also broaden the scope of target-based drug discovery strategies. Finally, the use of higher levels of theory will increase the accuracy of protein-ligand binding affinity predictions, resulting in better hit identification success rates as well as more efficient lead optimization processes.