Casiopeinas® as SARS-CoV-2 main protease (Mpro) inhibitors: a combined DFT, molecular docking and ONIOM approach

Abstract

Casiopeinas® are well-known planar copper compounds with potent anticancer activity; their general formula is [Cu(N–N)(L–L)]ⁿ⁺ (n = 1, 2), where N–N = 4,7-dimethyl-1,10-phenanthroline or 4,4′-dimethyl-2,2′-bipyridine and L–L = different bidentate chelates. CasIII-ia: [Cu(4,4′-dimethyl-2,2′-bipyridine)(acetylacetonate)]NO₃ is now being tested in clinical trials. In this work, a study of the potential inhibition of the SARS-CoV-2 main protease (M^pro) with Casiopeinas was carried out employing a combined computational strategy. Electronic structure DFT calculations indicate that the compounds present a square planar geometry and, in some cases, the coordination sphere has pseudo aromatic properties. Molecular docking examinations suggest that Casiopeinas form stable complexes with M^pro and therefore, can potentially inhibit this natural function by its bonding to the main amino acids of the active site. In this context, Casiopeinas disrupt the protease action more efficiently than the recognized inhibitors such as the N3 peptide or boceprevir. Hybrid QM:MM ONIOM calculations indicate that the copper atom is covalently bonded to glutamine 189 (Gln189), a key amino acid of the M^pro, the N–N donor could be participating in many π-interactions, and the atoms of the L–L fragment are bonded to the M^pro residues through classical and non-conventional hydrogen bonds. According to computational simulations, structural and electronic features of Casiopeinas promote their interaction with the enzyme and the potential disruption of the M^pro function.