Two novel oxetane containing lignans and a new megastigmane from Paronychia arabica and in silico analysis of them as prospective SARS-CoV-2 inhibitors

Abstract

The chemical characterization of the extract of the aerial parts of Paronychia arabica afforded two oxetane containing lignans, paronychiarabicine A (1) and B (2), and one new megastigmane, paronychiarabicastigmane A (3), alongside a known lignan (4), eight known phenolic compounds (5-12), one known elemene sesquiterpene (13) and one steroid glycoside (14). The chemical structures of the isolated compounds were constructed based upon the HRMS, 1D, and 2D-NMR results. The absolute configurations were established via NOESY experiments as well as experimental and TDDFT-calculated electronic circular dichroism (ECD). Utilizing molecular docking, the binding scores and modes of compounds 1-3 towards the SARS-CoV-2 main protease (M^pro), papain-like protease (PL^pro), and RNA-dependent RNA polymerase (RdRp) were revealed. Compound 3 exhibited a promising docking score (-9.8 kcal mol^-1) against SARS-CoV-2 M^pro by forming seven hydrogen bonds inside the active site with the key amino acids. The reactome pathway enrichment analysis revealed a correlation between the inhibition of GSK3 and GSK3B genes (identified as the main targets of megastigmane treatment) and significant inhibition of SARS-CoV-1 viral replication in infected Vero E6 cells. Our results manifest a novel understanding of genes, proteins and corresponding pathways against SARS-CoV-2 infection and could facilitate the identification and characterization of novel therapeutic targets as treatments of SARS-CoV-2 infection.

Fig. 1. Structures of the isolated compounds (1–14).

Fig. 2. ¹H–¹H COSY and HMBC of 1–3.

Fig. 3. Key NOESY results of 1–3.

Fig. 4. (a) Experimental electronic circular dichroism (ECD) in methanol of 1 (in black) and 2 (in blue), compared with the TDDFT-simulated ECD spectra of 1-7′R,8′R (in red) and 2-7′S,8′R (in green). (b) Experimental ECD in methanol of compound 3 (in black), compared with the TDDFT-simulated ECD spectra of 3-6S,9R, 3-6R,9R and 3-6R,9S.

Fig. 5. STRING protein–protein interaction (PPI) network for the top 20 targets for megastigmane (3) as a potent SARS inhibitor.

Fig. 6. (A) The reactome map illustration of disease pathways influenced by the top 20 gene targets responding to megastigmane (3) in terms of SARS-CoV-2 infection. The colours denote over-representation of that pathway in the input dataset. Light grey signifies pathways which are not significantly over-represented.

Fig. 7. SARS-CoV-2 infection pathway showing the targets (GSK3B; highlighted in dark yellow) in response to megastigmane (3) as a potent SARS-CoV-2 inhibitor. The interactor genes were highlighted in blue.

Fig. 8. Predicted docking score and binding mode of compounds 1–3 inside the active site of SARS-CoV-2 main protease (M^pro), papain-like protease (PL^pro) and RNA-dependent RNA polymerase (RdRp). Interactions: conventional hydrogen bond (green), carbon–hydrogen bond (pale green), pi–sigma and pi–pi (violet), pi–sulfur (yellow), alkyl and pi–alkyl (pale violet), unfavorable donor–donor (red), pi–lone-pair (lemon yellow).