Abstract
In modern drug discovery, virtual screening is an attractive and cost-effective approach, which is widely applied to filter chemical compound libraries for the identification of novel inhibitors. Epidermal growth factor receptor protein is a well reported anticancer molecular target due to its over expression and mutation in many solid tumours. The decline in epidermal growth factor receptor activity by small molecules has proved to be an effective treatment for cancer. To design inhibitors for this target, the crystal structures information of epidermal growth factor receptors, co-crystallized with its inhibitors, provide a gateway to perform receptor-based drug designing studies, whereas the inhibitors with their biological activity reported in literature provide information to carry out ligand-based drug designing studies. In the present study, the drug designing methods were strategically combined and used parallely on a library of 50,000 drug-like compounds from ChemDiv and ChemBridge database, for the selection of potential inhibitors of epidermal growth factor receptor. This resulted in the identification of 200 common hits, which were further pruned down to 87, based on the knowledge about the key interaction of known epidermal growth factor receptor inhibitors with Met793. These 87 hits were clustered into 12 different structural moieties. In vitro studies of some of these hits were also carried out in order to validate the screening approach. Further, the lead optimization studies were performed by analyzing the binding poses of all the identified structural moieties in order to ascertain the scope of modifications around these moieties. Molecular dynamics simulation studies further revealed some important residues of the target which may be helpful for providing stability to the enzyme-inhibitor complex. These findings could be very much helpful for a medicinal chemist to design a novel potent inhibitor of epidermal growth factor receptor.
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The authors acknowledge the Department of Biotechnology (DBT), India for the financial support from the projects GAP-0141 (DBT).
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Mahajan, P., Suri, N., Mehra, R. et al. Discovery of novel small molecule EGFR inhibitory leads by structure and ligand-based virtual screening. Med Chem Res 26, 74–92 (2017). https://doi.org/10.1007/s00044-016-1728-2
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DOI: https://doi.org/10.1007/s00044-016-1728-2