Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 17, Issue 18, Pages 6707-6714Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2009.07.061
Keywords
Ilimaquinone; S-Adenosylhomocysteine hydrolase; Inhibitor; Pharmacophore modeling
Funding
- National Institutes of Health [CA-66617]
- Ministry of Land, Transport and Maritime Affairs, Republic of Korea
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Effective inhibitors of S-adenosylhomocysteine hydrolase hold promise towards becoming useful therapeutic agents. Since most efforts have focused on the development of nucleoside analog inhibitors, issues regarding bioavailability and selectivity have been major challenges. Considering the marine sponge metabolite ilimaquinone was found to be a competitive inhibitor of S-adenosylhomocysteine hydrolase, new opportunities for developing selective new inhibitors of this enzyme have become available. Based on the activities of various hybrid analogs, SAR studies, pharmacophore modeling, and computer docking studies have lead to a predictive understanding of ilimaquinone's S-adenosylhomocysteine hydrolase inhibitory activities. These studies have allowed for the design and preparation of simplified structural variants possessing new furanoside bioisosteres with 100-fold greater inhibitory activities than that of the natural product. (C) 2009 Published by Elsevier Ltd.
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