Computational design of 1,2,3-triazole based inhibitors of SARS-CoV-2 main protease (Mpro)

AGUSTINA GRICH; CERUTTI JUAN PABLO; RIBONE SERGIO; DEHAEN WIM; QUEVEDO MARIO ALFREDO

Córdoba

Congreso; 6ta Reunión Internacional de Ciencias Farmacéuticas (RICiFa 2021); 2021

Universidad Nacional de Córdoba y Universidad Nacional de Rosario

The SARS-CoV-2 pandemic demands urgent action to obtain new pharmacological treatments, with the viral main protease (Mpro) attracting significant scientific attention as a therapeutic target. In this work, we design targeted covalent inhibitors (TCIs) of Mpro derived from the 1,2,3-triazole scaffold.Molecular docking methods were used to evaluate the binding of TCIs to Mpro. A training set including reported inhibitors (boceprevir, BCP; IC50: 8 µM and GC376, IC50: 0.15µM) and inactive compounds was used to validate the docking workflow. Inhibitors were also subjected to bioisosteric replacement with 1,2,3-triazole and further analyzed.The docking workflow reproduced the binding mode of BCP and GC376 to Mpro, with the corresponding 1,2,3-triazole derivatives binding in the reactive pose and also exhibiting higher affinity for the catalytic site. Inactive compounds were adequately predicted with non-reactive binding poses.Our results show that obtaining 1,2,3-triazole based TCIs arises as a promising strategy for the design of potent inhibitors of Mpro. This finding supports the bioisosteric replacement of the peptidic bond present in classic Mpro peptidomimetic protease inhibitors, and considering the versatility of triazole chemistry, grants the exploration of a wide chemical space for the design of inhibitors.