Natural versus synthetic inhibition of the PI3K pathway causing over-expression and reduced apoptosis to HER2 leading to ER+/HER2+ breast cancer

Amlan Chakraborty, Apoorv Gupta, Pranav Patni

Research output: Contribution to journalArticleResearch


Amplification or over-expression of the HER2 gene occurs in approximately 30% of breast cancers. HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis. It has been found that patients with ER+ (Estrogen receptor positive)/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit
the PI3K/AKT molecular pathway. The PI3K/AKT/mTOR pathway is an intracellular signalling pathway important in apoptosis and hence cancer. In case of ER+/HER2+ breast cancer this pathway is overactive, thus reducing apoptosis and allowing proliferation. Various natural compounds, including epigallocatechin gallate (EGCG), caffeine, curcumin, resveratrol and Taxol, have been found to inhibit PI3K pathway. Also, synthetic inhibitors like Wortmanin and
LY294002 has been found in inhibiting the PI3K pathway. Our study is based on designing natural inhibitors including epigallocatechin gallate (EGCG), caffeine, curcumin, resveratrol, taxol as well as for artificial inhibitors Wortmanin and LY294002; using ChemBioDraw Ultra 12.0 and ChemBio3D Ultra 12.0. Further we have done docking calculations using AutoDock 4.2 where Phosphoinositide
3-kinase was used as a receptor and was docked by all the seven ligands including the natural and the artificial. Screening was done using PyRx Virtual screening tool to find out the best Ligand (inhibitor) among the natural versus the synthetic, which binds and blocks the enzyme Phosphoinositide 3-kinase, which is part of this pathway and therefore, through inhibition, often results in tumour suppression. For docking the Lamarckian Genetic Algorithm has been followed. Based on the Gbindng value based on the scoring function designed it has been seen that Curcumin (Gbindng -679.46 Kcal/mol) has the best inhibitory effect followed by Taxol (Gbindng -638Kcal/mol).
Original languageEnglish
Number of pages5
JournalJournal of Applied Bioinformatics & Computational Biology
Publication statusPublished - 2015
Externally publishedYes

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