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In silico investigation of agonist activity of a structurally diverse set of drugs to hPXR using HM-BSM and HM-PNN

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Summary

The human pregnane X receptor (hPXR) plays a critical role in the metabolism, transport and clearance of xenobiotics in the liver and intestine. The hPXR can be activated by a structurally diverse of drugs to initiate clinically relevant drug-drug interactions. In this article, in silico investigation was performed on a structurally diverse set of drugs to identify critical structural features greatly related to their agonist activity towards hPXR. Heuristic method (HM)-Best Subset Modeling (BSM) and HM-Polynomial Neural Networks (PNN) were utilized to develop the linear and non-linear quantitative structure-activity relationship models. The applicability domain (AD) of the models was assessed by Williams plot. Statistically reliable models with good predictive power and explain were achieved (for HM-BSM, r 2=0.881, q 2LOO =0.797, q 2EXT =0.674; for HM-PNN, r 2=0.882, q 2LOO =0.856, q 2EXT =0.655). The developed models indicated that molecular aromatic and electric property, molecular weight and complexity may govern agonist activity of a structurally diverse set of drugs to hPXR.

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Authors and Affiliations

  1. School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 210029, China

    Yi-ming Zhang  (张一鸣) & Xiao Han  (韩 晓)

  2. School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China

    Mei-jia Chang  (常美佳) & Xu-shu Yang  (杨旭曙)

Authors
  1. Yi-ming Zhang  (张一鸣)
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  2. Mei-jia Chang  (常美佳)
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  3. Xu-shu Yang  (杨旭曙)
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  4. Xiao Han  (韩 晓)
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Corresponding authors

Correspondence to Xu-shu Yang  (杨旭曙) or Xiao Han  (韩 晓).

Additional information

The project was supported by grants from the Natural Science Research Project of Institution of Higher Education of Jiangsu Province (No. 11KJB180006) and National Natural Science Foundation of China (No. 21277074 and No. 81302458).

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Zhang, Ym., Chang, Mj., Yang, Xs. et al. In silico investigation of agonist activity of a structurally diverse set of drugs to hPXR using HM-BSM and HM-PNN. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 36, 463–468 (2016). https://doi.org/10.1007/s11596-016-1609-4

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  • DOI: https://doi.org/10.1007/s11596-016-1609-4

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