In silico analysis of echinocandins binding to the main proteases of coronaviruses PEDV (3CL(pro)) and SARS-CoV-2 (M(pro))

Vergoten, Gérard; Bailly, Christian

The porcine epidemic diarrhea virus (PEDV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are two highly pathogenic viruses causing tremendous damages to the swine and human populations, respectively. Vaccines are available to prevent contamination and to limit dissemination of these two coronaviruses, but efficient and widely affordable treatments are needed. Recently, four natural products targeting the 3C-like protease (3CL(pro)) of PEDV and inhibiting replication of the virus in vitro have been identified: tomatidine, epigallocatechin-3-gallate, buddlejasaponin IVb and pneumocandin B0. We have evaluated the interaction of these compounds with 3CL(pro) of PEDV and with the structurally similar main protease (M(pro)) of SARS-CoV-2. The molecular docking analysis indicated that the echinocandin-type lipopeptide pneumocandin B0 can generate much more stable complexes with both proteases compared to tomatidine. The empirical energy of interaction (ΔE) calculated with pneumocandin B0 bound to M(pro) is extremely high, comparable to that measured with known antiviral drugs. Pneumocandin B0 and its analogue capsofungin appeared a little less adapted to interact with 3CL(pro) compared to M(pro). In contrast, the antifungal drug micafungin bearing an unfused tricyclic side chain, emerges as a better ligand of 3CL(pro) of PEDV compared to M(pro) of SARS-CoV-2, based on our calculations. Collectively, the analysis underlines the benefit of echinocandin-type antifungal drugs as potential inhibitors of PEDV and SARS-CoV-2 main proteases. These clinically important antifungal natural products deserve further studies as antiviral agents.