Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41598-017-01491-z
Title: Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib
Authors: Kannan, S
Pradhan, M.R
Tiwari, G
Tan, W.-C
Chowbay, B 
Tan, E.H 
Tan, D.S.-W
Verma, C 
Keywords: afatinib
epidermal growth factor receptor
ligand
water
antagonists and inhibitors
binding site
chemistry
enzyme activation
genetics
human
molecular dynamics
mutation
Afatinib
Binding Sites
Enzyme Activation
ErbB Receptors
Humans
Ligands
Molecular Dynamics Simulation
Mutation
Water
Issue Date: 2017
Citation: Kannan, S, Pradhan, M.R, Tiwari, G, Tan, W.-C, Chowbay, B, Tan, E.H, Tan, D.S.-W, Verma, C (2017). Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib. Scientific Reports 7 (1) : 1540. ScholarBank@NUS Repository. https://doi.org/10.1038/s41598-017-01491-z
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. © 2017 The Author(s).
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/175187
ISSN: 20452322
DOI: 10.1038/s41598-017-01491-z
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