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In silico molecular docking study of natural compounds on wild and mutated epidermal growth factor receptor

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Abstract

The role played by overexpression of tyrosine kinase epidermal growth factor receptor (EGFR), the transmembrane receptor central to numerous cellular processes comprising cell migration, adhesion, apoptosis, and cell proliferation, has been highlighted in various cancers such as prostate, breast, lung, and ovarian cancers as well as in mutations in the EGFR kinase domain. Although many therapeutic approaches have targetted EGFR, the mutations occurring in the EGFR kinase domain including L858 EGFR and T790/L858R had led to the amplification of EGFR signals, consequently leading to increased cell proliferation and cell growth. The strategies involving the inhibition of EGFR L858 and T790M have been accredited with limited achievement in addition to being associated with unwanted adverse effects as a result of crosstalk of wild-type EGFR. All current EGFR tyrosine kinase inhibitors have been identified as ATP competitive inhibitors of wild-type EGFR possessing aniline and quinazoline moiety on the ligands skeleton. Our results obtained by performing molecular docking study on Maestro 9.3 molecular docking suite indicated that CID5280343 possesses better energy conformation against wild-type EGFR as well as two mutated EGFR. Moreover, it was discovered in this study that the natural compounds CID72276, CID5280445, CID441794, and CID72277 and InterBioScreen’s library STOCK1N-78657, STOCK1N-78976, and STOCK1N-78847 have better binding conformation against gatekeeper T790M mutated EGFR concluded to be brought about by means of flexible ligands/receptor-based molecular docking protocol. Miraculous features of these compounds are their various pharmacokinetic and pharmacodynamic parameters which were found to be satisfactory as drug-like molecules. This molecular docking study also summarizes docking free energy, protein–ligands interaction profile, and pharmacokinetic and pharmacodynamic parameter of lead molecules which were tremendously helpful in enhancing the activity of these natural compounds against EGFR.

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Acknowledgments

We would like to thank Vice Chancellor, Central University of Punjab, Bathinda, Punjab, (India) for supporting this study with infrastructural requirements. We also thank Professor P. Ramarao (Dean, Academic Affairs), Central University of Punjab, Bathinda, Punjab, India for his suggestions during the course that tremendously helped to improve this article. This study was also supported by a Senior Research Fellowship grant-in-aid from Indian Council of Medical Research (ICMR), Government of India awarded to PS. We also thank executive director, Schrödinger, for providing Maestro 9.3 technical support that has tremendously helped in this study.

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  1. Centre for Biosciences, School of Basic and Applied Science, Central University of Punjab, Bathinda, 151001, Punjab, India

    Pushpendra Singh & Felix Bast

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  1. Pushpendra Singh
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Correspondence to Felix Bast.

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Singh, P., Bast, F. In silico molecular docking study of natural compounds on wild and mutated epidermal growth factor receptor. Med Chem Res 23, 5074–5085 (2014). https://doi.org/10.1007/s00044-014-1090-1

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