Using Fragment Cocktail Crystallography To Assist Inhibitor Design of Trypanosoma brucei Nucleoside 2-Deoxyribosyltransferase

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• 作者：Jü ; rgen Bosch ; Mark A. Robien ; Christopher Mehlin ; Erica Boni ; Aaron Riechers ; Frederick S. Buckner ; Wesley C. Van Voorhis ; Peter J. Myler ; Elizabeth A. Worthey ; George DeTitta ; Joseph R. Luft ; A
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：October 5, 2006
• 年：2006
• 卷：49
• 期：20
• 页码：5939 - 5946
• 全文大小：735K
• 年卷期：v.49,no.20(October 5, 2006)
• ISSN：1520-4804

文摘

The 1.8 Å resolution de novo structure of nucleoside 2-deoxyribosyltransferase (EC 2.4.2.6) fromTrypanosoma brucei (TbNDRT) has been determined by SAD^a phasing in an unliganded state and severalligand-bound states. This enzyme is important in the salvage pathway of nucleoside recycling. To identifynovel lead compounds, we exploited "fragment cocktail soaks". Out of 304 compounds tried in 31 cocktails,four compounds could be identified crystallographically in the active site. In addition, we demonstrated thatvery short soaks of ~10 s are sufficient even for rather hydrophobic ligands to bind in the active site groove,which is promising for the application of similar soaking experiments to less robust crystals of other proteins.