Computational study of EGFR inhibition: molecular dynamics studies on the active and inactive protein conformations
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ORIGINAL PAPER
Computational study of EGFR inhibition: molecular dynamics studies on the active and inactive protein conformations Napat Songtawee & M. Paul Gleeson & Kiattawee Choowongkomon
Received: 24 November 2011 / Accepted: 2 August 2012 # Springer-Verlag 2012
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. Electronic supplementary material The online version of this article (doi:10.1007/s00894-012-1559-0) contains supplementary material, which is available to authorized users. N. Songtawee : K. Choowongkomon Department of Biochemistry, Faculty of Science, Kasetsart University, 50 Phaholyothin Rd, Chatuchak, Bangkok 10900, Thailand M. P. Gleeson (*) Department of Chemistry, Faculty of Science, Kasetsart University, 50 Phaholyothin Rd, Chatuchak, Bangkok 10900, Thailand e-mail: [email protected] K. Choowongkomon (*) Center for Advanced Studies in Tropical Natural Resources, NRU-KU, Kasetsart University, 50 Phaholyothin Rd, Chatuchak, Bangkok 10900, Thailand e-mail: [email protected]
Keywords EGFR . Kinase . Molecular dynamics . AMBER force field . GROMACS . Gefitinib . Lapatinib 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
Introduction Protein kinases are an important class of therapeutic targets in drug discovery. At present, eight kinase inhibitors are currently marketed as anti-cancer treatments [1], and it has been estimated that approximately one-third of all pharmaceutical research projects are dedicated to such targets [2]. Three of the eight marketed kinase drugs target the epidermal growth factor receptor (EGFR), also known as ErbB1 kinase. A wealth of biochemical and structural information has been generated on this target, offering us considerable insight into the structure, function and inhibition of this important therapeutic target class [3–5
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