Nonequilibrium Alchemical Simulations for the Development of Drugs Against Covid-19

With the world plagued by the coronavirus pandemic, efficient automated protocols for a reliable in silico estimate of the binding strength of compounds vs SARS-CoV2-related biological targets are urgently needed. The consensus computational pipeline in drug development starts from triaging via docking tools of data-driven generated libraries of compounds followed by Molecular Dynamics (MD) techniques on a subset of the best scoring ligands. In this context, absolute binding free energy determination via MD is a crucial and challenging intermediate step, preceding the drug optimization process, using efficient alchemical MD techniques on strictly congeneric series. Here we describe an alchemical MD technique based on nonequilibrium thermodynamics capable of delivering in few hours on a modern HPC platform reliable estimates of the absolute binding free energies in drug–receptor systems. The methodology can be combined with well established alchemical relative binding free energy calculations providing an automatable workflow for drug optimization starting from a set of chemically distant ligands.