Casiopeinas (R) as SARS-CoV-2 main protease (M-pro) inhibitors: a combined DFT, molecular docking and ONIOM approach
Por:
Reina, Miguel, Gabriel Talavera-Contreras, Luis, Figueroa-DePaz, Yeshenia, Ruiz-Azuara, Lena, Felipe Hernandez-Ayala, Luis
Publicada:
5 jul 2022
Resumen:
Casiopeinas (R) 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 pi-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.
Filiaciones:
Reina, Miguel:
Univ Nacl Autonoma Mexico, Fac Quim, Dept Quim Inorgan & Nucl, Lab Quim Inorgan Med, Ave Univ 3000, Ciudad De Mexico 04510, Mexico
Gabriel Talavera-Contreras, Luis:
Univ Nacl Autonoma Mexico, Fac Quim, Dept Quim Inorgan & Nucl, Lab Quim Inorgan Med, Ave Univ 3000, Ciudad De Mexico 04510, Mexico
Figueroa-DePaz, Yeshenia:
Univ Nacl Autonoma Mexico, Fac Quim, Dept Quim Inorgan & Nucl, Lab Quim Inorgan Med, Ave Univ 3000, Ciudad De Mexico 04510, Mexico
Ruiz-Azuara, Lena:
Univ Nacl Autonoma Mexico, Fac Quim, Dept Quim Inorgan & Nucl, Lab Quim Inorgan Med, Ave Univ 3000, Ciudad De Mexico 04510, Mexico
Felipe Hernandez-Ayala, Luis:
Univ Nacl Autonoma Mexico, Fac Quim, Dept Quim Inorgan & Nucl, Lab Quim Inorgan Med, Ave Univ 3000, Ciudad De Mexico 04510, Mexico
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