How exascale computing can shape drug design: A perspective from multiscale QM/MM molecular dynamics simulations and machine learning-aided enhanced sampling algorithms.

Molecular simulations are an essential asset in the first steps of drug design campaigns. However, the requirement of high-throughput limits applications mainly to qualitative approaches with low computational cost, but also low accuracy. Unlocking the potential of more rigorous quantum mechanical/molecular mechanics (QM/MM) models combined with molecular dynamics-based free energy techniques could have a tremendous impact. Indeed, these two relatively old techniques are emerging as promising methods in the field. This has been favored by the exponential growth of computer power and the proliferation of powerful data-driven methods. Here, we briefly review recent advances and applications, and give our perspective on the impact that QM/MM and free-energy methods combined with machine learning-aided algorithms can have on drug design.