TY  - JOUR
A1  - Verma, Nidhi
A1  - Rai, Amit Kumar
A1  - Kaushik, Vibha
A1  - Brünnert, Daniela
A1  - Chahar, Kirti Raj
A1  - Pandey, Janmejay
A1  - Goyal, Pankaj
T1  - Identification of gefitinib off-targets using a structure-based systems biology approach; their validation with reverse docking and retrospective data mining
JF  - Scientific Reports
N2  - Gefitinib, an EGFR tyrosine kinase inhibitor, is used as FDA approved drug in breast cancer and non-small cell lung cancer treatment. However, this drug has certain side effects and complications for which the underlying molecular mechanisms are not well understood. By systems biology based in silico analysis, we identified off-targets of gefitinib that might explain side effects of this drugs. The crystal structure of EGFR-gefitinib complex was used for binding pocket similarity searches on a druggable proteome database (Sc-PDB) by using IsoMIF Finder. The top 128 hits of putative off-targets were validated by reverse docking approach. The results showed that identified off-targets have efficient binding with gefitinib. The identified human specific off-targets were confirmed and further analyzed for their links with biological process and clinical disease pathways using retrospective studies and literature mining, respectively. Noticeably, many of the identified off-targets in this study were reported in previous high-throughput screenings. Interestingly, the present study reveals that gefitinib may have positive effects in reducing brain and bone metastasis, and may be useful in defining novel gefitinib based treatment regime. We propose that a system wide approach could be useful during new drug development and to minimize side effect of the prospective drug.
KW  - gefitinib
KW  - side effects
KW  - drug
KW  - off-targets
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167621
VL  - 6
IS  - 33949
ER  -