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A comparative study of AutoDock and PMF scoring performances, and SAR of 2-substituted pyrazolotriazolopyrimidines and 4-substituted pyrazolopyrimidines as potent xanthine oxidase inhibitors

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Abstract

4-Alkylidenehydrazino-1H-pyrazolo[3,4-d]pyrimidines, 4-arylmethylidenehydrazino-1H-pyrazolo[3,4-d]pyrimidines, and 2-substituted 7H-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidines as potential xanthine oxidase inhibitors were docked into the active site of the bovine milk xanthine dehydrogenase using two scoring functions involved in AutoDock 3.05 and the CAChe 6.1.10. The correlation coefficiency obtained between the AutoDock binding energy and IC50 of the inhibitors was better than that obtained by the CAChe-PMF docking score. Many ligands exhibited one to four hydrogen bonds within the active site, where the detected hydrogen bonds by CAChe was identified quantitatively in the docked conformation by using MOPAC 2002. These ligands were docked into a long, narrow channel of the enzyme leading to the molybdopterin active moiety, with hydrogen bonding and electrostatic interaction between the planar aromatic moiety of the ligand and the enzyme. Furthermore, SAR among inhibitors was investigated, which revealed that the oxo group of pyrazolopyrimidine analogs is essential for its activity and the tricyclic derivatives are shown to be more potent than bicyclic ones. The mode of interaction of the docked inhibitors was described in details.

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Acknowledgments

This work was supported in part by Academic Frontier Grants-in-aid of the Ministry of Education, Science and Technology in Japan and we are grateful to the people in charge for the grant assignment.

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Authors and Affiliations

  1. Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-Naka, Okayama, 700-8530, Japan

    Hamed I. Ali, Takayuki Fujita & Tomohisa Nagamatsu

  2. Faculty of Pharmaceutical Sciences, Center for Area Research and Development (CARD), Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan

    Eiichi Akaho

Authors
  1. Hamed I. Ali
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  2. Takayuki Fujita
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  3. Eiichi Akaho
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  4. Tomohisa Nagamatsu
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Correspondence to Eiichi Akaho.

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Ali, H.I., Fujita, T., Akaho, E. et al. A comparative study of AutoDock and PMF scoring performances, and SAR of 2-substituted pyrazolotriazolopyrimidines and 4-substituted pyrazolopyrimidines as potent xanthine oxidase inhibitors. J Comput Aided Mol Des 24, 57–75 (2010). https://doi.org/10.1007/s10822-009-9314-z

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  • DOI: https://doi.org/10.1007/s10822-009-9314-z

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