MOLECULAR MODELLING APPROACHES AND CHEMOGENOMIC PROFILING OF NATURALLY OCCURRING COMPOUND AS POTENTIAL EGFR-TK INHIBITOR
V. Badireenath Konkimalla
School of Biological Sciences, NISER, Bhubaneswar, Orissa, India
Abstract:
Development of drug resistance and severe side effects are the crucial factors limiting cure rates in cancer chemotherapy urging an immediate need for improved therapeutics. Bioactive compounds from medicinal plants represent a valuable resource for novel anticancer drugs. A library of 531 naturally occuring compounds derived from traditional Chinese medicine (TCM) that were cytotoxic to atleast forty of the 60 cancer cell lines of the National Cancer Institute, USA was established. The structure files of these 531 compounds were used for docking studies.
From comparative genomic hybridization, EGFR was identified as prognostic marker due to gain of chromosome band 7p12 in 19 out of 35 patient samples. The 531 TCM compounds were docked on the erlotinib-bound EGFR tyrosine kinase domain crystal structure template. Docking efficiency were compared to that of erlotinib in terms of binding energy. Dicentrine was identified to be a potential compound and further experimentally validated on cell lines transfected with different constructs of EGFR. Microarray and RT-PCR was performed to obtain an insight on the regulated pathway.
In conclusion, we expect that such interdisciplinary approach of biomarker identification, docking approaches and experimental validation represent an attractive strategy for identification of bioactive lead molecules.