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Exploring the crizotinib resistance mechanism of NSCLC with the L1196M mutation using molecular dynamics simulation

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Abstract

Crizotinib is an anticancer tyrosine kinase inhibitor that is approved for use as a first-line treatment for some non-small-cell lung cancers. L1196M is the most frequently observed mutation in NSCLC patients. This mutation, known as the gatekeeper mutation in the ALK kinase domain, confers resistance to crizotinib by sterically blocking the binding of the drug. However, the molecular mechanism of crizotinib resistance caused by the L1196M mutation is still unclear. Molecular dynamics simulation was therefore utilized in this study to investigate the mechanism by which the L1196M mutation may affect crizotinib resistance. Our results suggest that larger fluctuations in some important regions of the mutant complex compared to the wild-type complex may contribute to the resistance of the mutant complex to crizotinib. Also, mutation-induced alterations to the secondary structure of the complex as well as unstable hydrogen-bonding patterns in the A-loop and P-loop regions decrease the total binding energy of the complex. This study therefore provides a molecular explanation for the resistance to crizotinib caused by the L1196M mutation, which could aid the design of more efficient and selective drugs.

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Abbreviations

RTKs:

Receptor tyrosine kinase

NSCLC:

Non-small-cell lung cancer

EML4:

Echinoderm microtubule-associated protein-like 4

FDA:

Food and Drug Administration

GAFF:

Generalized AMBER force field

SD:

Steepest descent

CG:

Conjugated gradient

PME:

Particle mesh Ewald

RMSD:

Root-mean-square deviation

RMSF:

Root-mean-square fluctuation

ALK:

Anaplastic lymphoma kinase

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Author notes

  1. Maryam Kay and Fariba Dehghanian contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Islamic Republic of Iran

    Maryam Kay

  2. Division of Genetics, Department of Biology, Faculty of Science, University of Isfahan, Isfahan, Islamic Republic of Iran

    Fariba Dehghanian

Authors
  1. Maryam Kay
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  2. Fariba Dehghanian
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Correspondence to Maryam Kay.

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Kay, M., Dehghanian, F. Exploring the crizotinib resistance mechanism of NSCLC with the L1196M mutation using molecular dynamics simulation. J Mol Model 23, 323 (2017). https://doi.org/10.1007/s00894-017-3495-5

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