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Title: Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib
Authors: Kannan, Srinivasaraghavan
Pradhan, Mohan R.
Tiwari, Garima
Tan, Wei-Chong
Chowbay, Balram
Tan, Eng Huat
Tan, Daniel Shao-Weng
Verma, Chandra
Keywords: Drug discovery
Computational biophysics
Issue Date: 2017
Source: Kannan, S., Pradhan, M. R., Tiwari, G., Tan, W.-C., Chowbay, B., Tan, E. H., et al. (2017). Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib. Scientific Reports, 7, 1540-.
Series/Report no.: Scientific Reports
Abstract: Small molecules targeting the EGFR tyrosine kinase domain have been used with some success at treating patients with non-small cell lung cancer driven by activating mutations in the kinase domain. The initial class of inhibitors displaced ATP noncovalently but were rendered ineffective due to the development of resistance mutations in the kinase domain. These were overcome by the development of covalent inhibitors such as afatinib which also bind in the ATP pocket. However pooled analysis of two recent clinical trials LUX-3 and LUX-6 demonstrated an unprecedented overall survival benefit of afatinib over chemotherapy for the EGFR19del, but not the EGFRL858R. In the current study we use modelling and simulations to show that structural constraints in EGFR19del deletion result in significantly attenuated flexibilities in the binding pocket resulting in strong hydrogen and halogen bonds with afatinib in the EGFR19del; these constraints are modulated by buried water and result in the differential affinities of afatinib for the different mutants. SNP analysis of residues surrounding the buried water points to the likelihood of further differential effects of afatinib and provides a compelling case for investigating the effects of the SNPs towards further stratification of patients for ensuring the most effective use of afatinib.
ISSN: 2045-2322
DOI: 10.1038/s41598-017-01491-z
Schools: School of Biological Sciences 
Rights: © 2017 The Author(s) (Nature Publishing Group). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
Fulltext Permission: open
Fulltext Availability: With Fulltext
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