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

[Image: see text] 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 2Z demonstrated a higher binding affinity for 3CL(pro) than 2E, 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 2Z and 2E compared to the reference HIV-1 protease inhibitor, lopinavir. Besides, DFT calculations demonstrated the more energetic stability of 2E compared to 2Z, which justifies the difficulty in isolating the Z-isomer in a pure form, where it readily isomerizes to the E-isomer.