In-silico & In-vitro identification of structure-activity relationship pattern of Serpentine & Gallic acid targeting PI3Kγ as potential anticancer target.

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In-silico & In-vitro identification of structure-activity relationship pattern of Serpentine & Gallic acid targeting PI3Kγ as potential anticancer target.

Curr Cancer Drug Targets. 2017 Mar 30;:

Authors: Sharma P, Shukla A, Kalani K, Dubey V, Luqman S, Srivastava SK, Khan F

Abstract
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 (PI3K) is a family of related intracellular signal transducer enzymes or lipid kinases that regulate different cellular processes involved in cancer. In the studied work, anticancer potential of two active plant secondary metabolites, namely gallic acid and serpentine was evaluated against PI3Ks, especially gamma isoform and compared with the wortmannin, a steroid metabolite of the fungi and a non-specific covalent known inhibitor of PI3Ks, based on in-silico QSAR, molecular docking, eADMET and in-vitro activity. To identify the molecular reason behind the similar target based activity of these shikimate pathway metabolites on PI3Ks, structure-activity relationship study was performed. we developed predictive quantitative activity structural relationship model applying multiple linear regression which reveals identification of structural properties regulating the inhibitory activity of serpentine and gallic acid on PI3Kγ. The model exhibited acceptable statistical parameter such as regression coefficient (r2 = 0.76), cross-validation coefficient (r2CV = 0.72) and test set validation coefficient (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 against anticancer target PI3Ks. The identified chemical features were amide group count, amine group count, secondary amine group count, highest occupied molecule orbital (HOMO) energy and valence connectivity index (order 2). To gain more insight into their mode of action, molecular docking study was performed. In-silico ADME and toxicity estimation was also done for pharmacokinetic and bioavailability compliance.

PMID: 28359246 [PubMed - as supplied by publisher]

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