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In-silico & In-vitro Identification of Structure-Activity Relationship Pattern of Serpentine & Gallic Acid Targeting
Pooja Sharma1, Aparna Shukla1, Komal Kalani2
1Metabolic & Structural Biology Department, Plant Biology Division, CSIR-Central Institute of Medicinal & Aromatic Plants (CIMAP), P.O.-CIMAP, Kukrail Picnic Spot Road, Lucknow-226015 (Uttar Pradesh). India.
Background:
Natural products showed anticancer activity and often induce apoptosis or autophagy in cancer cells through the PI3K/Akt/mTOR signaling pathways. The potential of natural products as PI3Ks inhibitors has been reported, which suggest PI3Ks a promising anticancer target. Phosphoinositide 3-kinase is a family of related intracellular signal transducer enzymes or lipid kinases that regulate different cellular processes involved in cancer.
Objective:
To identify the molecular reason behind the similar target based activity of selected shikimate pathway metabolites on PI3Kγ, a detail structure-activity relationship study was performed.
Method:
In the studied work, anticancer potential of plant molecules gallic acid and serpentine was evaluated against PI3Kγ isoform and compared with wortmannin, a steroid metabolite of the fungi and a non-specific covalent known inhibitor of PI3Ks by using in-silico QSAR, docking, ADMET, chemical isolation from plant, NMR and in-vitro activity.
Results:
A predictive QSAR model was developed by applying multiple linear regression which revealed identification of key structural properties regulating the inhibitory activity of serpentine and gallic acid on PI3Kγ. The model exhibited acceptable statistical parameters such as r2 0.76, r2CV 0.72, and q2 0.55. Structural elucidation was done through NMR studies. Predicted activities were further evaluated through in-vitro testing of gallic acid and serpentine targeting PI3Kγ.
Conclusion:
The identified chemical features modulating the activity were amide, amine, and secondary amine groups counts, highest occupied molecule orbital (HOMO) energy and valence connectivity index (order 2). In-silico ADME and toxicity risk assessment was done for pharmacokinetic and bioavailability compliance evaluation.