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Identification of diverse dipeptidyl peptidase IV inhibitors via structure-based virtual screening

Journal of Molecular Modeling volume 18, pages 4033–4042 (2012)Cite this article

Abstract

Dipeptidyl peptidase IV (DPP4) is an important target for the treatment of type II diabetes mellitus. Inhibition of DPP4 will improve glycemic control in such patients by preventing the rapid breakdown and thereby prolonging the physiological actions of incretin hormones. Known DPP4 inhibitors (including marketed drugs and those drug candidates) appear to share similar structural features: the cyanopyrrolidine moieties, the xanthenes/pyrimidine parts and amino-like linkages. In this study, a multi-step virtual screening strategy including both rigid and flexible docking was employed to search for novel structures with DPP4 inhibition. From SPECS database, consisting of over 190,000 commercially available compounds, 99 virtual hits were picked up and 15 of them were eventually identified to have DPP4 inhibitory activities at 5 ~ 50 μM. Diverse structures of our compounds were out of usual structural categories. Hence a pharmacophore model was built to further explore their common binding features on the enzyme. The results provided a new pathway for the discovery of DPP4 inhibitors and would be helpful for further optimization of DPP4 inhibitors.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grants 30973642 and 90813005), the Shanghai Committee of Science and Technology (Grant 11DZ2260600), the Fundamental Research Funds for the Central Universities (Grant 0914035), the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant 20090074120012), and the Innovation Program of Shanghai Municipal Education Commission (Grant 10ZZ41).

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Affiliations

  1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China

    Cui Li, Weiqiang Lu, Chunhua Lu, Wen Xiao, Xu Shen, Jin Huang, Guixia Liu & Yun Tang

  2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China

    Xu Shen

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  1. Cui Li
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  2. Weiqiang Lu
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  3. Chunhua Lu
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  4. Wen Xiao
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  5. Xu Shen
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  6. Jin Huang
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Correspondence to Jin Huang or Guixia Liu.

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Li, C., Lu, W., Lu, C. et al. Identification of diverse dipeptidyl peptidase IV inhibitors via structure-based virtual screening. J Mol Model 18, 4033–4042 (2012). https://doi.org/10.1007/s00894-012-1394-3

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  • DOI: https://doi.org/10.1007/s00894-012-1394-3

Keywords

  • Dipeptidyl peptidase IV
  • Molecular docking
  • Pharmacophore modeling
  • Type II diabetes
  • Virtual screening