Investigating the promising SARS-CoV-2 main protease inhibitory activity of secoiridoids isolated from <i>Jasminum humile</i>; <i>in silico</i> and <i>in virto</i> assessments with structure-activity relationship
Creators: name: Al-Karmalawy, Ahmed A.
name: Alnajjar, Radwan
name: Elmaaty, Ayman Abo
name: Binjubair, Faizah A.
name: Al-Rashood, Sara T.
name: Mansour, Basma S.
name: Elkamhawy, Ahmed
name: Eldehna, Wagdy M.
name: Mansour, Khaled Ahmed
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Cell Biology
subject: Molecular Biology
subject: Pharmacology
subject: Chemical Sciences not elsewhere classified
subject: Ecology
subject: FOS: Biological sciences
subject: Biological Sciences not elsewhere classified
subject: Infectious Diseases
subject: FOS: Health sciences
subject: Virology

description: The proteolytic enzyme 3 C-like protease (3Clpro or M<sup>pro</sup>) 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 <i>Jasminum humile</i> (<i>J. humile</i>) were examined <i>in vitro</i> and <i>in silico</i> against the SARS-CoV-2 M<sup>pro</sup>. 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 (<b>T1</b>) displayed the most significant activity against SARS-CoV-2 with IC<sub>50</sub> = 29.36 µg/mL. Besides, the fractions (<b>Fr1</b> and <b>Fr3</b>) showed good activity against the SARS-CoV-2 with IC<sub>50</sub> values of 70.42, and 73.09 µg/mL, respectively. Then, the SARS-CoV-2 M<sup>pro</sup> inhibitory assay was utilized to emphasize the inhibitory potential of the investigated isolates. <b>MJN</b>, <b>JMD</b>, and <b>IJM</b> candidates displayed prominent M<sup>pro</sup> inhibitory potentials with IC<sub>50</sub> = 30.44, 30.24, and 56.25 µM, respectively. Moreover, molecular docking of the identified seven compounds against the M<sup>pro</sup> of SARS-CoV-2 showed that the five secoiridoids achieved superior results. <b>MJN</b>, <b>JSM</b>, <b>IJM</b>, and <b>JMD</b> showed higher affinities towards the M<sup>pro</sup> target compared to the co-crystallized antagonist. Furthermore, the most active complexes (<b>MJN</b>, <b>JSM</b>, <b>IJM</b>, and <b>JMD-M<sup>pro</sup></b>) were subjected to MD simulations run for 150 ns and MM-GBSA calculations, compared to the co-crystallized inhibitor (<b>O6K-M<sup>pro</sup></b>). Finally, the SAR study clarified that <b>JMD</b> achieved the best anti-SARS-CoV-2 M<sup>pro</sup> activity followed by <b>MJN</b>. Communicated by Ramaswamy H. Sarma Communicated by Ramaswamy H. Sarma Seven isolates from <i>J. humile</i>, besides different extracts, were examined both <i>in vitro</i> and <i>in silico</i>. Anti-SARS-CoV-2 using the MTT assay and anti-SARS-CoV-2 Mpro inhibitory assay were performed. Compounds <b>MJN</b>, <b>JMD</b>, and <b>IJM</b> 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.