Effects of single nucleotide polymorphisms on the binding of afatinib to EGFR : a potential patient stratification factor revealed by modeling studies
The anticancer drug afatinib has been found to be more effective at inhibiting the oncogenic EGFR mutant exon 19 deletion (19del) over the oncogenic EGFR mutant L858R. The underlying mechanism has been hypothesized to result from differences in structural constraints introduced by the mutations and...
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| Format: | Journal Article |
| Language: | English |
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2020
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| Online Access: | https://hdl.handle.net/10356/144576 |
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| author | Kannan, Srinivasaraghavan Tan, Daniel Shao-Weng Verma, Chandra Shekhar |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Kannan, Srinivasaraghavan Tan, Daniel Shao-Weng Verma, Chandra Shekhar |
| author_sort | Kannan, Srinivasaraghavan |
| collection | NTU |
| description | The anticancer drug afatinib has been found to be more effective at inhibiting the oncogenic EGFR mutant exon 19 deletion (19del) over the oncogenic EGFR mutant L858R. The underlying mechanism has been hypothesized to result from differences in structural constraints introduced by the mutations and stabilizing interactions afforded by a buried water molecule in 19del (Kannan, S.; et al. Sci. Rep. 2017, 7, 1540). The COSMIC cancer database is mined for EGFR sequences to discover that several mutations in the form of Single nucleotide polymorphisms (SNPs) line this hydration cavity. In this work, the effects of these SNPs on the affinity of afatinib for EGFRWT and oncogenic mutants EGFRL858R and EGFR19del were studied using free energy perturbation and thermodynamic Integration calculations. The simulations reveal that several SNPs have significant effects on the affinity of afatinib for the mutant EGFRs carrying the SNPs and may thus have clinical implications relating to emergence of resistance to afatinib, thus potentially impacting the choice of EGFR inhibitors in the clinic. |
| first_indexed | 2024-10-01T05:33:18Z |
| format | Journal Article |
| id | ntu-10356/144576 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:33:18Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | ntu-10356/1445762023-02-28T16:56:54Z Effects of single nucleotide polymorphisms on the binding of afatinib to EGFR : a potential patient stratification factor revealed by modeling studies Kannan, Srinivasaraghavan Tan, Daniel Shao-Weng Verma, Chandra Shekhar School of Biological Sciences Bioinformatics Institute, A*STAR Science::Biological sciences Free Energy Peptides And Proteins The anticancer drug afatinib has been found to be more effective at inhibiting the oncogenic EGFR mutant exon 19 deletion (19del) over the oncogenic EGFR mutant L858R. The underlying mechanism has been hypothesized to result from differences in structural constraints introduced by the mutations and stabilizing interactions afforded by a buried water molecule in 19del (Kannan, S.; et al. Sci. Rep. 2017, 7, 1540). The COSMIC cancer database is mined for EGFR sequences to discover that several mutations in the form of Single nucleotide polymorphisms (SNPs) line this hydration cavity. In this work, the effects of these SNPs on the affinity of afatinib for EGFRWT and oncogenic mutants EGFRL858R and EGFR19del were studied using free energy perturbation and thermodynamic Integration calculations. The simulations reveal that several SNPs have significant effects on the affinity of afatinib for the mutant EGFRs carrying the SNPs and may thus have clinical implications relating to emergence of resistance to afatinib, thus potentially impacting the choice of EGFR inhibitors in the clinic. Agency for Science, Technology and Research (A*STAR) Economic Development Board (EDB) National Research Foundation (NRF) Accepted version The authors thank the National Super Computing Centre (NSCC) for the computing facilities. D.S.W.T is supported by the NMRC clinical-scientist award (NMRC/CSA/007/2016). The authors thank A*STAR for support; S.Kannan is partly supported by an IAF-PP grant H18/01/a0/015 funded by A*STAR/NRF/EDB, Singapore. 2020-11-13T02:42:20Z 2020-11-13T02:42:20Z 2018 Journal Article Kannan, S., Tan, D. S.-W., & Verma, C. S. (2019). Effects of Single Nucleotide Polymorphisms on the Binding of Afatinib to EGFR: A Potential Patient Stratification Factor Revealed by Modeling Studies. Journal of Chemical Information and Modeling, 59(1), 309–315. doi:10.1021/acs.jcim.8b00491 1549-9596 https://hdl.handle.net/10356/144576 10.1021/acs.jcim.8b00491 30481018 1 59 309 315 en Journal of chemical information and modeling This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of chemical information and modeling, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jcim.8b00491 application/pdf |
| spellingShingle | Science::Biological sciences Free Energy Peptides And Proteins Kannan, Srinivasaraghavan Tan, Daniel Shao-Weng Verma, Chandra Shekhar Effects of single nucleotide polymorphisms on the binding of afatinib to EGFR : a potential patient stratification factor revealed by modeling studies |
| title | Effects of single nucleotide polymorphisms on the binding of afatinib to EGFR : a potential patient stratification factor revealed by modeling studies |
| title_full | Effects of single nucleotide polymorphisms on the binding of afatinib to EGFR : a potential patient stratification factor revealed by modeling studies |
| title_fullStr | Effects of single nucleotide polymorphisms on the binding of afatinib to EGFR : a potential patient stratification factor revealed by modeling studies |
| title_full_unstemmed | Effects of single nucleotide polymorphisms on the binding of afatinib to EGFR : a potential patient stratification factor revealed by modeling studies |
| title_short | Effects of single nucleotide polymorphisms on the binding of afatinib to EGFR : a potential patient stratification factor revealed by modeling studies |
| title_sort | effects of single nucleotide polymorphisms on the binding of afatinib to egfr a potential patient stratification factor revealed by modeling studies |
| topic | Science::Biological sciences Free Energy Peptides And Proteins |
| url | https://hdl.handle.net/10356/144576 |
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