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.