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Identification of 2,4-diarylaminopyrimidine analogues as ALK inhibitors by using 3D-QSAR, molecular docking, and molecular dynamics simulations

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Abstract

Anaplastic lymphoma kinase (ALK) is a particularly promising target for the development of small molecule anti-cancer drugs. In the present study, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 60 ALK inhibitors to build three-dimensional quantitative structure–activity relationship models. Both the ligand-based resultants of CoMFA (r 2 0.970, q 2 0.660) and CoMSIA (r 2 0.979, q 2 0.623) models exhibited good predictability. The resulting contour maps illustrated the regions where interactive fields may affect the activity. Molecular docking was then performed to explore the interactions between these inhibitors and the ALK-4DCE protein. A few key residues (His32, Gly31, Gly169, Asp170, Val35, Ala100, Pro160, Lys50, and Leu30) at the binding site of 4DCE were identified. Molecular dynamics simulation further verified the reliability. The information acquired in this work not only provides a better appreciation of interactions between these molecules and the ALK receptor but could also be applied to design more effective ALK inhibitors.

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Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (21172148, 21472126, and 21502117) and Shanghai Municipal Education Commission (Plateau Discipline Construction Program).

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Authors and Affiliations

  1. School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, People’s Republic of China

    Dan-Dan Li, Fu-Long Wu, Zhong-Hua Wang, Lei-Lei Huang, Yan Yin & Fan-Hong Wu

  2. Shanghai Engineering Research Center of Pharmaceutical Progress, Shanghai, 201203, China

    Zhong-Hua Wang

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  1. Dan-Dan Li
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  2. Fu-Long Wu
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  3. Zhong-Hua Wang
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  4. Lei-Lei Huang
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  5. Yan Yin
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Correspondence to Zhong-Hua Wang or Fan-Hong Wu.

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Li, DD., Wu, FL., Wang, ZH. et al. Identification of 2,4-diarylaminopyrimidine analogues as ALK inhibitors by using 3D-QSAR, molecular docking, and molecular dynamics simulations. Monatsh Chem 148, 1711–1725 (2017). https://doi.org/10.1007/s00706-017-1999-4

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  • DOI: https://doi.org/10.1007/s00706-017-1999-4

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