Abstract:
Insulin like growth factor-1 receptor (IGF-1R) along with highly homologous insulin receptor IR is integral component of cell proliferation, growth and survival and apoptosis protection. However, overexpression of IGF-1R and IR-A, and increased bioavailability of insulin-like growth factors (IGF-1 and IGF-2) in various cancers is a well-known phenomenon of tumorogenesis. Various strategies have been proposed in the past to evade cell proliferation during cancer. It includes targeting IGF-IR with selective antibodies and inhibition of its tyrosine kinase domain with small molecules. However, the results of these investigations remained gloomy and only few compounds reached in the clinical trials that ultimately failed to inhibit growth of human cancers. It is might be due to the fact that compensatory cross talk between IGF-1R and IR compromise drug efficacy during selective inhibition of IGF-1R. Recent molecular dynamics simulations of various co-crystalized ligand revealed that majority of the inhibitors bind to the basal state of the kinase hinge region thus, preventing the kinase activation. Therefore, development of small molecular antagonists impeding the tyrosine kinase domains of IGF-IR and IR-A has been advocated as a promising concept to evade cell proliferation and drug resistance in cancer chemotherapy. Therefore, present thesis, various in silico tools has been utilized to explore the binding hypothesis and molecular basis of interaction of tyrosine kinase domain of IR and IGF-1R with small molecular inhibitors. Briefly, combined ligand (3D QSAR, GRIND) as well as structure based techniques (Molecular Docking) have been utilized to identify dual 3D structural features of tyrosine kinase domain inhibitors.
Our results demonstrated the importance of two hydrogen bond acceptors, two hydrogen bond donors at a certain distance from each other as well as from molecular boundaries plays
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significant role in dual inhibition of IR and IGF-IR. Our Pharmacophore models were used for the virtual screening of ChemBridge and WDI databases that resulted in eight potential hits as dual inhibitors of IR and IGF-1R. The current study will pave the way toward designing potential drug candidates with better Administration, Distribution, Metabolism and Elimination (ADME) properties and reduced toxicity against cancer.
