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Computational study of EGFR inhibition: molecular dynamics studies on the active and inactive protein conformations

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Abstract

The structural diversity observed across protein kinases, resulting in subtly different active site cavities, is highly desirable in the pursuit of selective inhibitors, yet it can also be a hindrance from a structure-based design perspective. An important challenge in structure-based design is to better understand the dynamic nature of protein kinases and the underlying reasons for specific conformational preferences in the presence of different inhibitors. To investigate this issue, we performed molecular dynamics simulation on both the active and inactive wild type epidermal growth factor receptor (EGFR) protein with both type-I and type-II inhibitors. Our goal is to better understand the origin of the two distinct EGFR protein conformations, their dynamic differences, and their relative preference for Type-I inhibitors such as gefitinib and Type-II inhibitors such as lapatinib. We discuss the implications of protein dynamics from a structure-based design perspective.

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Abbreviations

EGFR:

Epidermal growth factor receptor

G-loop:

Glycine-rich loop

A-loop:

Activation loop

R-spine:

Regulatory spine

H-cluster:

Hydrophobic cluster

DFG motif:

Asp-Phe-Gly conserved motif

HRD motif:

His-Arg-Asp conserved motif

PDB:

Protein data bank

MD:

Molecular dynamics

RMSD:

Root average square deviation

RMSF:

Root average square fluctuation

SD:

Standard deviation

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Acknowledgments

This work was supported by the Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission and the Thailand Research Fund grants RMU5180032 (KC) and RSA5480016 (MPG). We wish to express our gratitude for the use of Laboratory for Computational and Applied Chemistry (LCAC) research facilities at Kasetsart University provided by the National Center of Excellence in Petroleum, Petrochemical Technology and Advanced Materials. M.P.G. is grateful for the support of the Faculty of Science at KU and Associate Professor Supa Hannongbua in particular. N.S. was supported by a grant under the program Strategic Scholarships for Frontier Research Network for the Join PhD Program Thai Doctoral degree from the Office of the Higher Education Commission, Ministry of Education, Thailand.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Science, Kasetsart University, 50 Phaholyothin Rd, Chatuchak, Bangkok, 10900, Thailand

    Napat Songtawee & Kiattawee Choowongkomon

  2. Department of Chemistry, Faculty of Science, Kasetsart University, 50 Phaholyothin Rd, Chatuchak, Bangkok, 10900, Thailand

    M. Paul Gleeson

  3. Center for Advanced Studies in Tropical Natural Resources, NRU-KU, Kasetsart University, 50 Phaholyothin Rd, Chatuchak, Bangkok, 10900, Thailand

    Kiattawee Choowongkomon

Authors
  1. Napat Songtawee
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  2. M. Paul Gleeson
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  3. Kiattawee Choowongkomon
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Corresponding authors

Correspondence to M. Paul Gleeson or Kiattawee Choowongkomon.

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Songtawee, N., Gleeson, M.P. & Choowongkomon, K. Computational study of EGFR inhibition: molecular dynamics studies on the active and inactive protein conformations. J Mol Model 19, 497–509 (2013). https://doi.org/10.1007/s00894-012-1559-0

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  • DOI: https://doi.org/10.1007/s00894-012-1559-0

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