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Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors

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Abstract

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models for a series of thiazolone derivatives as novel inhibitors bound to the allosteric site of hepatitis C virus (HCV) NS5B polymerase were developed based on CoMFA and CoMSIA analyses. Two different conformations of the template molecule and the combinations of different CoMSIA field/fields were considered to build predictive CoMFA and CoMSIA models. The CoMFA and CoMSIA models with best predictive ability were obtained by the use of the template conformation from X-ray crystal structures. The best CoMFA and CoMSIA models gave q 2 values of 0.621 and 0.685, and r 2 values of 0.950 and 0.940, respectively for the 51 compounds in the training set. The predictive ability of the two models was also validated by using a test set of 16 compounds which gave r 2pred values of 0.685 and 0.822, respectively. The information obtained from the CoMFA and CoMSIA 3D contour maps enables the interpretation of their structure-activity relationship and was also used to the design of several new inhibitors with improved activity.

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Acknowledgement

This work was supported by the Program for New Century Excellent Talents in University (No. NCET-07-0399).

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Authors and Affiliations

  1. Department of Chemistry, Lanzhou University, Lanzhou, 730000, China

    Beilei Lei, Juan Du, Shuyan Li, Yueying Ren & Xiaojun Yao

  2. School of Pharmacy, Lanzhou University, Lanzhou, 730000, China

    Huanxiang Liu

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  1. Beilei Lei
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  2. Juan Du
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  3. Shuyan Li
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  4. Huanxiang Liu
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Correspondence to Xiaojun Yao.

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Lei, B., Du, J., Li, S. et al. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors. J Comput Aided Mol Des 22, 711–725 (2008). https://doi.org/10.1007/s10822-008-9230-7

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  • DOI: https://doi.org/10.1007/s10822-008-9230-7

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