4.7 Article

Identification of small molecule compounds with higher binding affinity to guanine deaminase (cypin) than guanine

期刊

BIOORGANIC & MEDICINAL CHEMISTRY
卷 18, 期 18, 页码 6748-6755

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.07.054

关键词

Guanine deaminase; Purine metabolism; Molecular dynamics; Molecular docking; Kinetic; Assay

资金

  1. National Science Foundation (NSF) [DGE-0333196, IBN-0548543]
  2. NIH [5 T32 MH019957]
  3. Busch Biomedical Grant
  4. New Jersey Governor's Council on Autism Pilot Grant
  5. March of Dimes Foundation [1-FY04-107, 1-FY08-464]
  6. National Library of Medicine [2G08LM06230-03A1]

向作者/读者索取更多资源

Guanine deaminase (GDA; cypin) is an important metalloenzyme that processes the first step in purine catabolism, converting guanine to xanthine by hydrolytic deamination. In higher eukaryotes, GDA also plays an important role in the development of neuronal morphology by regulating dendritic arborization. In addition to its role in the maturing brain, GDA is thought to be involved in proper liver function since increased levels of GDA activity have been correlated with liver disease and transplant rejection. Although mammalian GDA is an attractive and potential drug target for treatment of both liver diseases and cognitive disorders, prospective novel inhibitors and/or activators of this enzyme have not been actively pursued. In this study, we employed the combination of protein structure analysis and experimental kinetic studies to seek novel potential ligands for human guanine deaminase. Using virtual screening and biochemical analysis, we identified common small molecule compounds that demonstrate a higher binding affinity to GDA than does guanine. In vitro analysis demonstrates that these compounds inhibit guanine deamination, and more surprisingly, affect GDA (cypin)-mediated microtubule assembly. The results in this study provide evidence that an in silico drug discovery strategy coupled with in vitro validation assays can be successfully implemented to discover compounds that may possess therapeutic value for the treatment of diseases and disorders where GDA activity is abnormal. (C) 2010 Elsevier Ltd. All rights reserved.

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