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. Keywords: Receptor tyrosine kinases, ErbB1, ErbB2, Natural products, Pharmacophore, Docking, Cancer therapy
Highlights
The incidence of lung cancer worldwide is 13 %
receptor tyrosine kinases (RTKs) belong to epidermal growth factor receptor family and there four structurally related family members are ErbB1, ErbB2, ErbB3, and ErbB4
Three shared features - two hydrophobic and one hydrogen bond acceptor were obtained from both the drugs (Fig 1), which were considered as a query for virtual screening
Summary
The incidence of lung cancer worldwide is 13 %. The highest incidence is in developed countries, in North America and Europe, and is less common in developing and underdeveloped countries [1,2,3]. The etiology of this malady is linked with the anomaly in around 26 genes, among them receptor tyrosine kinases (RTKs), are involved in lung cancer proliferation [4,5]. ErbB1 and ErbB2 are predominant in lung cancer [2,6,7,8] These kinases have an extracellular ligand binding domain, a single hydrophobic transmembrane domain, and an intracellular tyrosine kinase domain [9]. The tyrosine kinase domain, which is structurally conserved in both
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