Versisterol, a new endophytic steroid with 3CL protease inhibitory activity from Avicennia marina (Forssk.) Vierh

Abstract

A new epoxy ergostane sterol, named versisterol, was isolated from Aspergillus versicolor, an endophytic fungus from Avicennia marina. The structure of the isolated compound was deduced by means of one- and two-dimensional NMR and high-resolution mass spectrometry. The absolute stereochemistry was elucidated by NOESY analysis, and experimental and calculated time-dependent density functional theory (TD-DFT) circular dichroism spectroscopy. Versisterol inhibited 3CL protease (3CL^pro) with an IC₅₀ value of 2.168 ± 0.09 μM. Binding affinities and molecular interactions of versisterol towards 3CL^pro were scrutinized and compared to lopinavir with the help of the combination of docking computations and molecular dynamics (MD) simulation. In silico calculations demonstrated a comparable binding affinity of versisterol with a docking score of -9.4 kcal mol^-1, and MM-GBSA binding energy over 200 ns MD simulation of -29.1 kcal mol^-1, with respect to lopinavir (-9.8 and -32.2 kcal mol^-1, respectively). These findings suggested that versisterol can be an auspicious prototype for developing new 3CL^pro drug candidates against COVID-19.

Fig. 1. The structure of versisterol isolated from A. vsersicolor.

Fig. 2. Key COSY and HMBC correlations for versisterol.

Fig. 3. Key NOESY correlations for versisterol.

Fig. 4. Experimental and TD-DFT-simulated electronic circular dichroism (ECD) in methanol for versisterol.

Fig. 5. 3D and 2D representations as well as the predicted docking scores of (i) versisterol and (ii) lopinavir with 3-chymotrypsin-like protease (3CL^pro).

Fig. 6. Decomposition of MM-GBSA binding energies for the inspected inhibitors complexed with 3-chymotrypsin-like protease (3CL^pro) throughout 200 ns MD simulations.

Fig. 7. Estimated MM-GBSA binding energy per-frame for versisterol (in black), and lopinavir (in light blue) with 3-chymotrypsin-like protease (3CL^pro) throughout 200 ns MD simulations.

Fig. 8. Root-mean-square deviation (RMSD) of the backbone atoms from the starting structure for versisterol (in black) and lopinavir (in light blue) with the 3-chymotrypsin-like protease (3CL^pro) throughout 200 ns MD simulations.