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 (3CLpro), IC50 = 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 3CLpro. Compound 2Z demonstrated a higher binding affinity for 3CLpro 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.
© 2022 The Authors. Published by American Chemical Society.