RESUMEN
The global coronavirus (COVID-19) outbreak has prompted scientists to discover a cure for the disease. So far, phosphorus-based drugs have been proposed. These drugs have good inhibitory activity against the main protease (Mpro). Hence, in order to introduce a group of inhibitors the coronavirus, 51 compounds containing different mono, bis, and tetra phosphonates as Remdesivir derivatives, 32 of which are new, were synthesized and characterized by 31P, 13C, and 1H NMR and IR spectroscopy. Their biological activities were also investigated by Molecular Docking, QSAR, and Pharmacophore. Van der Waals, hydrogen bonding, and hydrophobic interactions were studied for all compounds as well as binding energy (â³G, Kcal/mole) and the inhibitory constant Ki (µM) obtained by Molecular Docking. The results showed that the topology of the ligands and the change of the different groups attached to them can be effective in the placement position in the active site of the enzyme (Glu 166 and Gln 189). And bisphosphonates have a high interaction tendency with Mpro COVID-19. Compound L24 was identified as the best inhibitor with the -6.38 kcal/mol binding energy. The quantitative structure-activity relationship (QSAR) findings demonstrated that the polarity and topology of molecules in all phosphonate derivatives were important parameters affecting the effecting on the binding energy and inhibitory ability of compounds. The DFT and pharmacophore results are in good accordance with those of QSAR and molecular docking. This study can be helpful to gain a better understanding of the interactions between the Mpro of virus and its inhibitors in order to attain drugs with more effect on coronavirus (COVID-19).
RESUMEN
Coronaviruses have posed a persistent threat to human health over the last two decades. Despite the accumulated knowledge about coronavirus-related pathogens, development of an effective treatment for its new variant COVID-19 is highly challenging. For the highly-conserved and main coronavirus protease 3CLpro, dimerization is known to be essential for its catalytic activity and thereby for virus proliferation. Here, we assess the potential of short peptide segments to disrupt dimerization of the 3CLpro protease as a route to block COVID-19 proliferation. Based on the X-ray structure of the 3CLpro dimer, we identified the SPSGVY126QCAMRP dodecapeptide segment as overlapping the hotspot regions on the 3CLpro dimer interface. Using computational blind docking of the peptide to the 3CLpro monomer, we found that the SPSGVY126QCAMRP peptide has favourable thermodynamic binding (ΔG= -5.93 kcal/mol) to the hotspot regions at the 3CLpro dimer interface. Importantly, the peptide was also found to preferentially bind to the hotspot regions compared to other potential binding sites lying away from the dimer interface (ΔΔG=-1.31 kcal/mol). Docking of peptides corresponding to systematic mutation of the V125 and Y126 residues led to the identification of seven peptides, SPSGHAQCAMRP, SPSGVTQCAMRP, SPSGKPQCAMRP, SPSGATQCAMRP, SPSGWLQCAMRP, SPSGAPQCAMRP and SPSGHPQCAMRP, that outperform the wild-type SPSGVY126QCAMRP peptide in terms of preferential binding to the 3CLpro dimer interface. These peptides have the potential to disrupt 3CLpro dimerization and therefore could provide lead structures for the development of broad spectrum COVID-19 inhibitors.Communicated by Ramaswamy H. Sarma.