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

• Published in: Journal of medicinal chemistry Vol. 49; no. 20; pp. 5939 - 5946
• Main Authors: Bosch, Jürgen, Robien, Mark A, Mehlin, Christopher, Boni, Erica, Riechers, Aaron, Buckner, Frederick S, Van Voorhis, Wesley C, Myler, Peter J, Worthey, Elizabeth A, DeTitta, George, Luft, Joseph R, Lauricella, Angela, Gulde, Stacey, Anderson, Lori A, Kalyuzhniy, Oleksandr, Neely, Helen M, Ross, Jenni, Earnest, Thomas N, Soltis, Michael, Schoenfeld, Lori, Zucker, Frank, Merritt, Ethan A, Fan, Erkang, Verlinde, Christophe L. M. J, Hol, Wim G. J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 05-10-2006
• Subjects: Amino Acid Sequence; Animals; Benzyl Alcohols - chemistry; Benzyl Alcohols - pharmacology; Binding Sites; Biological and medical sciences; Crystallography, X-Ray; Indoles - chemistry; Indoles - pharmacology; Isoquinolines - chemistry; Isoquinolines - pharmacology; Ligands; Medical sciences; Miscellaneous; Models, Molecular; Molecular Sequence Data; Molecular Structure; Pentosyltransferases - antagonists & inhibitors; Pentosyltransferases - chemistry; Pharmacology. Drug treatments; Quinolines - chemistry; Quinolines - pharmacology; Structure-Activity Relationship; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei brucei - enzymology; Kinetoplastida; Protozoa; Isoquinoline derivatives; Molecular structure; Enzyme; Transferases; Active site; Glycosyltransferases; Sequence alignment; Enzyme inhibitor; Nucleoside deoxyribosyltransferase; Quinoline derivatives; Crystallography; X ray diffraction; In vitro; Biological activity; Trypanosoma brucei; Pentosyltransferases; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060429m

The 1.8 Å resolution de novo structure of nucleoside 2-deoxyribosyltransferase (EC 2.4.2.6) from Trypanosoma brucei (TbNDRT) has been determined by SAD a phasing in an unliganded state and several ligand-bound states. This enzyme is important in the salvage pathway of nucleoside recycling. To identify novel 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 that very 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.