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Interaction of Hydroxychloroquine with SARS-CoV2 Functional Proteins Using All-atoms Non-equilibrium Alchemical Simulations

submitted on 15.04.2020, 13:28 and posted on 17.04.2020, 09:38 by Piero Procacci, Marina Macchiagodena, Marco Pagliai, Guido Guarnieri, Francesco Iannone
The paper presents an accurate in silico measurement of the dissociation constant of HCQ on three important SARS-Cov2 protein targets, namely the main protease (3CLpro) and the Papain-like protease (PLpro) and the RNA dependent RNA polimerase (RdRp), using the recently the released PDB stuructures of these protein. Calculations are done using state-of-the art force fields and advanced simulation methodologies combining enhanced sampling and nonequilibrium techniques amenable to massive parallelization on a dedicated HPC cluster.

We have shown that HCQ may act as a mild inhibitor for all the three viral proteins, with potency increasing in the series PLpro, 3CLpro, RdRp. By analyzing the bound state configurations, we were able to improve the potency for the 3CLpro target, designing a novel HCQ-inspired compound, named PMP329, with predicted nanomolar activity. If confirmed in vitro, our results provide a convincing molecular rationale for the use of HCQ or of strictly related derivatives in the treatment of Covid-19.


Email Address of Submitting Author


University of Florence and ENEA



ORCID For Submitting Author


Declaration of Conflict of Interest

there are no conflict of interests