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Computer-aided de novo ligand design and docking/molecular dynamics study of Vitamin D receptor agonists

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Abstract

1α,25(OH)2D3, which is directly mediated by the vitamin D receptor (VDR), exerts a wide variety of biological actions. However, the treatment with 1α,25(OH)2D3 is limited because of its side effects. Many analogs and several nonsteroidal mimics with potent biological activity have been reported so far, and our rationale for designing the VDR agonists was on the basis of computer-aided drug design method by de novo design of A-ring and C/D-ring position of 1α,25(OH)2D3. Pyrimidine-2,4-diamine was selected as A-ring, and naphthalene and benzene were chosen as C/D-ring. By linking different components, a virtue compound library was obtained. To evaluate the contribution to activity of each component, we performed a series of automated molecular docking operations. Results revealed that the 19-dimethyl derivatives (the C-19 position correspond to C-20 in 1α,25(OH)2D3) show the favorable docking affinity to VDR. Moreover, the docking results are quite robust when further validated by molecular dynamics simulations. In addition, by free energy analysis using molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method, the driving force of the binding between VDR and the ligands is proved to be hydrophobic interactions. Thus, a possible strategy to design new series of VDR agonists is proposed. The strategy can be successfully applied to explain the high potential activities of the 19-dimethyl derivatives. It is anticipated that the findings reported here may provide useful information for designing effective VDR agonists as well as the therapeutic treatment of VDR-related diseases.

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Acknowledgments

We gratefully acknowledge the support from Project of Undergraduate Educational Reform & Capacities in Tianjin University (No. 200904050).

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Authors and Affiliations

  1. Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, People’s Republic of China

    Xiu-Long Shen, Jing Wei & Qing-Zhi Gao

  2. Teijin Institute for Biomedical Research, 4-3-2 Asahigaoka, Hino, Tokyo, 191–8512, Japan

    Midori Takimoto-Kamimura

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  1. Xiu-Long Shen
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  2. Midori Takimoto-Kamimura
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  3. Jing Wei
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  4. Qing-Zhi Gao
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Correspondence to Jing Wei or Qing-Zhi Gao.

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Shen, XL., Takimoto-Kamimura, M., Wei, J. et al. Computer-aided de novo ligand design and docking/molecular dynamics study of Vitamin D receptor agonists. J Mol Model 18, 203–212 (2012). https://doi.org/10.1007/s00894-011-1066-8

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  • DOI: https://doi.org/10.1007/s00894-011-1066-8

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