Investigating the promising SARS-CoV-2 main protease inhibitory activity of secoiridoids isolated from Jasminum humile; in silico and in virto assessments with structure-activity relationship

The proteolytic enzyme 3 C-like protease (3Clpro or Mpro) is considered the most important target for SARS-CoV-2 which could be attributed to its crucial role in viral maturation and/or replication. Besides, natural phytoconstituents from plant origin are always promising lead compounds in the drug discovery area. Herein, the previously isolated and identified seven compounds from Jasminum humile (J. humile) were examined in vitro and in silico against the SARS-CoV-2 Mpro. First, the Vero E6 cells were utilized to pursue the potential of the investigated compounds (both in fractions and individual isolates) using the MTT assay. The total extract (T1) displayed the most significant activity against SARS-CoV-2 with IC50 = 29.36 µg/mL. Besides, the fractions (Fr1 and Fr3) showed good activity against the SARS-CoV-2 with IC50 values of 70.42, and 73.09 µg/mL, respectively. Then, the SARS-CoV-2 Mpro inhibitory assay was utilized to emphasize the inhibitory potential of the investigated isolates. MJN, JMD, and IJM candidates displayed prominent Mpro inhibitory potentials with IC50 = 30.44, 30.24, and 56.25 µM, respectively. Moreover, molecular docking of the identified seven compounds against the Mpro of SARS-CoV-2 showed that the five secoiridoids achieved superior results. MJN, JSM, IJM, and JMD showed higher affinities towards the Mpro target compared to the co-crystallized antagonist. Furthermore, the most active complexes (MJN, JSM, IJM, and JMD-Mpro) were subjected to MD simulations run for 150 ns and MM-GBSA calculations, compared to the co-crystallized inhibitor (O6K-Mpro). Finally, the SAR study clarified that JMD achieved the best anti-SARS-CoV-2 Mpro activity followed by MJN.Communicated by Ramaswamy H. Sarma.HIGHLIGHTSSeven isolates from J. humile, besides different extracts, were examined both in vitro and in silico.Anti-SARS-CoV-2 using the MTT assay and anti-SARS-CoV-2 Mpro inhibitory assay were performed.Compounds MJN, JMD, and IJM displayed prominent SARS-CoV-2 Mpro inhibition.Molecular docking, molecular dynamics simulations, and MM-GBSA calculations were carried out.SAR study was conducted on the isolated compounds.