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Structural Insights into Characterizing Binding Sites in Epidermal Growth Factor Receptor Kinase Mutants

  • Zheng Zhao
    Zheng Zhao
    Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22904, United States of America
    More by Zheng Zhao
    Orcidhttp://orcid.org/0000-0003-1453-3230
  • , 
  • Lei Xie
    Lei Xie
    Department of Computer Science, Hunter College, The City University of New York, New York, New York 10065, United States of America
    The Graduate Center, The City University of New York, New York, New York 10016, United States of America
    More by Lei Xie
  • , and 
  • Philip E. Bourne*
    Philip E. Bourne
    Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22904, United States of America
    Data Science Institute, University of Virginia, Charlottesville, Virginia 22904, United States of America
    *Phone: (434) 924-6867. E-mail: [email protected]
    More by Philip E. Bourne
Cite this: J. Chem. Inf. Model. 2019, 59, 1, 453–462
Publication Date (Web):December 24, 2018
https://doi.org/10.1021/acs.jcim.8b00458
Copyright © 2018 American Chemical Society
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    Abstract

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    Over the last two decades epidermal growth factor receptor (EGFR) kinase has become an important target to treat nonsmall cell lung cancer (NSCLC). Currently, three generations of EGFR kinase-targeted small molecule drugs have been FDA approved. They nominally produce a response at the start of treatment and lead to a substantial survival benefit for patients. However, long-term treatment results in acquired drug resistance and further vulnerability to NSCLC. Therefore, novel EGFR kinase inhibitors that specially overcome acquired mutations are urgently needed. To this end, we carried out a comprehensive study of different EGFR kinase mutants using a structural systems pharmacology strategy. Our analysis shows that both wild-type and mutated structures exhibit multiple conformational states that have not been observed in solved crystal structures. We show that this conformational flexibility accommodates diverse types of ligands with multiple types of binding modes. These results provide insights for designing a new generation of EGFR kinase inhibitor that combats acquired drug-resistant mutations through a multiconformation-based drug design strategy.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jcim.8b00458.

    • Figures S1–9 illustrate the C- and R-spine analysis, the volume and shape of the binding pockets, the analysis of different MD trajectories, PCA, the class-D1 binding pocket, the different between the class-D1 binding site and all the other six classes of EGFR binding sites, and the screened top complex. Tables S1–6 describe the EGFR kinase structure data set, the volume of every subpocket conformation, the similarity list, the top similar complex, the index and the pdb id of every kinase structure, and the classes of the binding mode, respectively (DOCX)

    • Class-D1 EGFR kinase structure (PDB)

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