Article Details

COMPUTATIONAL EVIDENCE TO INHIBITION OF IGF-1R TYROSINE KINASE BY WITHANONE FOR CANCER THERAPY | Original Article

Varsha P. Wadegaonkar, Harshada H Pilley, Prasad A. Wadegaonkar*, in Current Trends in Biomedical & Life Sciences | Life Sciences

ABSTRACT:

Insulin-like growth factor receptor (IGF-1R) signaling plays a critical role in normal cell growth, cancer development and progression. IGF-1R, a tetrameric Tran’s membrane receptor tyrosine kinase, is particularly important in the establishment and maintenance of the transformed phenotype, in mediating proliferation, and for the survival of tumor cells with anchorage-independent growth. Studies have concentrated on modulating IGF-1R tyrosine kinase activity by targeting its intracellular kinase domain. Toxicity of available drugs and drug resistance development by cancer cells in recent years has made a cure difficult and challenging. Tertiary structure of IGF 1R with a carbon linked proline isostere inhibitor was obtained from protein data Bank with a resolution of 2.14Å. The compound withanone was virtually docked with the active site of tyrosine kinase domain of IGF 1R using flexible protein docking approach. Withanone shows hydrophobic interaction with tyr1131, a site for auto-phosphorylation. Withanone showed good binding affinity of -9.5056 kcal/mol. Present study elucidates the possible mechanism by which withanone induces apoptosis and controls the growth of cancer cells in vivo and in vitro. Withanone docked at the same site as that of reference ligand, i.e., an inhibitor LGX was bound to the kinase domain of the IGF 1R. This supports the hypothesis that the withanone can interfere with signalling process of IGF 1R.