Eryngium creticum L.: Chemical Characterization, SARS-CoV-2 Inhibitory Activity, and In Silico Study.

Phytochemical investigation of Eryngium creticum L. has resulted in isolation of five compounds, including four compounds that are reported from the plant for the first time. Compound 1 was identified as ( E )-rosmarinic acid, meanwhile, compound 2 was isolated as an ( E / Z )-rosmarinic acid mixture. Interestingly, the E / Z -isomeric mixture was about 4 times as active as the single E -isomer toward the severe acute respiratory syndrome coronavirus 2 3-chymotrypsin-like protease (3CL pro ), IC 50 = 6.062 and 25.75 μM, respectively. Utilizing combined molecular docking and molecular dynamics (MD) techniques, the binding affinities and features of the isolated compounds were evaluated against 3CL pro . Compound 2 Z demonstrated a higher binding affinity for 3CL pro than 2 E , with docking scores of -8.9 and -8.5 kcal/mol and MM-GBSA/150 ns MD binding energies of -26.5 and -22.1 kcal/mol, respectively. This justifies the superior activity of the E / Z -isomeric mixture versus the single E -isomer. Structural and energetic analyses revealed the stability of 2 Z and 2 E compared to the reference HIV-1 protease inhibitor, lopinavir. Besides, DFT calculations demonstrated the more energetic stability of 2 E compared to 2 Z , which justifies the difficulty in isolating the Z -isomer in a pure form, where it readily isomerizes to the E -isomer.