Carotane sesquiterpenes from Ferula vesceritensis: in silico analysis as SARS-CoV-2 binding inhibitors

Abstract

Two sesquiterpenes, 8α-anisate-dauc-4-ene-3,9-dione (webiol anisate) (1) and 10α-acetoxy-6α-benzoate-jaeschkeanadiol (2) as well as, ten known analogues (3-10), and two sesquiterpene coumarins (11-12) were isolated from an organic root extract of Ferula vesceritensis (Fam. Apiaceae). Chemical structures were elucidated based on IR, 1D- and 2D-NMR and HRMS, spectroscopic analyses. With molecular overlap observed between two protease inhibitors that are being examined as anti-COVID-19 drugs, and sesquiterpenes isolated here, metabolite molecular docking calculations were made using the main protease (M^pro), which is required for viral multiplication as well as RNA-dependent RNA polymerase (RdRp). In silico binding-inhibition analysis predicted that select F. vesceritensis sesquiterpenes can bind to these enzymes required for viral replication. Structures of the isolated constituents were also consistent with the chemo-systematic grouping of F. vesceritensis secondary metabolites with other Ferula species.

Fig. 1. Isolated compounds from Ferula vesceritensis.

Fig. 2. Selected ¹H–¹H COSY (−) and HMBC () correlations of 1,2.

Fig. 3. 2D and 3D representations of interactions of 1, darunavir, and lopinavir with proximal amino acid residues of the SARS-CoV-2 main protease (M^pro).

Fig. 4. 2D and 3D representations of interactions of 1, darunavir, and lopinavir with proximal amino acid residues of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp).

Fig. 5. (A) Venn diagram analysis of 1 and SARS disease genes and (B) STRING PPI network for the top 10 targets identified by network analyzer for 1 as potent SARS-CoV-2 inhibitor.