Synthesis, Characterization, and Molecular Docking of Casiopeinas® with Dipeptides as Secondary Ligand; Potential Inhibitors of SARS-Cov-2 Transcendental Proteins

• Published in: Journal of the Mexican Chemical Society 2024-01, Vol.68 (1), p.29-55
• Main Authors: Talavera Contreras, Luis Gabriel, Hernández-Ayala, Luis Felipe, Gómez-Vidales, Virginia, Villar-Cuevas, María Lourdes, Ruiz Azuara, Lena
• Format: Article
• Language: English
• ISSN: 1870-249X; 2594-0317
• DOI: 10.29356/jmcs.v68i1.1849

In this work, the synthesis and characterization of fourteen Casiopeinas® are presented, whose general formulae is [Cu(N-N)(L-L)]NO3, where N-N are 2,2´-bipirydine and 1,10-phenanthroline and some of its methylated derivatives, L-L represent the dipeptides L-Tyrosil-Glycinate or Glycil-L-Tyrosinate. Spectroscopic characterization and DFT studies determine the square planar geometry for the coordination compounds, as well as the influence of the dipeptide on the molecular arrangement of ternary copper(II) compounds. In addition, a molecular docking study was carried out against transcendental proteins of the SARS-CoV-2 virus such as main protease (Mpro) and the RBD Spike-ACE2 complex. Docking studies indicate that all compounds can produce stable adducts with Mpro, obtaining ΔGU values (-9.57 to -6.62 Kcal/mol) similar and superior to those presented by the reference inhibitors [boceprevir (-8.44 Kcal/mol) and remdesivir (-6.62 kcal/mol)], while for the RBD Spike-ACE2 complex obtaining ΔGU values of five (-6.69 to -4.61 in C-terminal region) and three (-8.27 to -6.34 in central region) orders of magnitude higher than those presented by the controls (Boceprevir: ΔGU=-1.98 in C-terminal, ΔGU=-4.97 in central region, Remdesivir: ΔGU=Non interactions in C-terminal, ΔGU=-3.37 in central region). π-alkyl interactions, π -cation, π -stacking, as well as hydrogen bonds and salt bridge bonds occur between the proteins and Casiopeinas®. In Mpro, interactions occur in aminoacids that are part of the enzymes catalytic site. Casiopeinas® interact at the interface of the RDB Spike-ACE2 complex in both, C-terminal and central regions. The obtained results position Casiopeinas® as potential candidates protein inhibitors of the virus that causes COVID-19.   Resumen. En este trabajo, se presenta la síntesis y caracterización de 14 Casiopeinas®, cuya fórmula general es [Cu(N-N)(L-L)]NO3, donde N-N son 2,2´-bipiridina y derivados metilados o 1,10-fenantrolina y análogos con grupos metilo, L-L representan a los dipéptidos L-Tirosil-Glicinato o Glicil-L-Tirosinato. Mediante estudios espectroscópicos y de DFT determinan la geometría cuadrada de los compuestos sintetizados, así como la influencia del dipéptido en el arreglo molecular de los compuestos ternarios de cobre(II). Complementariamente, se realizó un estudio de docking molecular ante proteínas trascendentales del virus SARS-CoV-2 como lo son la proteasa principal (MPro o nsps-3) y el complejo RBD Spike-ACE2. Estudios de d