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 M pro ) 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 M pro . 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 IC 50 = 29.36 µg/mL. Besides, the fractions ( Fr1 and Fr3 ) showed good activity against the SARS-CoV-2 with IC 50 values of 70.42, and 73.09 µg/mL, respectively. Then, the SARS-CoV-2 M pro inhibitory assay was utilized to emphasize the inhibitory potential of the investigated isolates. MJN , JMD , and IJM candidates displayed prominent M pro inhibitory potentials with IC 50 = 30.44, 30.24, and 56.25 µM, respectively. Moreover, molecular docking of the identified seven compounds against the M pro of SARS-CoV-2 showed that the five secoiridoids achieved superior results. MJN , JSM , IJM , and JMD showed higher affinities towards the M pro target compared to the co-crystallized antagonist. Furthermore, the most active complexes ( MJN , JSM , IJM , and JMD-M pro ) were subjected to MD simulations run for 150 ns and MM-GBSA calculations, compared to the co-crystallized inhibitor ( O6K-M pro ). Finally, the SAR study clarified that JMD achieved the best anti-SARS-CoV-2 M pro activity followed by MJN .Communicated by Ramaswamy H. Sarma.