A holistic in silico approach to develop novel inhibitors targeting ErbB1 and ErbB2 kinases

Abstract

Purpose: To design a dual inhibitor of natural origin capable of targeting ErbB1 and ErbB2 kinases for the treatment of lung cancer. Method: Advanced In silico drug designing techniques were explored in this study. Sequence and structure analysis of ErbB1 and ErbB2 was followed by three dimensional (3D) pharmacophore. The generated model was used for molecular docking simulation studies for predicting the best natural dual inhibitors, the selected inhibitors were subjected to absorption, distribution, metabolism, excretion and toxicology (ADME/Tox) prediction. Results: The results confirmedfive phytochemicals, viz. hyoscyamide, cannabisin F, cochinchinenene D, cannabisin E, and heliotropamide and five FDA approved drugs namely fesoterodine, antrafenine, fluspirilene, posaconazole, and iloprost to be potential inhibitors of both ErbB1 and ErbB2. The shortlisted compounds from both the panels were showing better MolDock score than the two reference drugs (Lapatinib and Afatinib). Conclusion: The 3D pharmacophore modelling and molecular docking simulations gave us ten compounds that successfully exploited dual inhibition of ErbB1 and ErbB2. With 8 and 12 hydrogen bonds with ErbB1 and ErbB2 respectively cannabisin F showed best interaction of all.