Using fragment cocktail crystallography to assist inhibitor design of Trypanosoma brucei nucleoside 2-deoxyribosyltransferase

Jürgen 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, Angela Lauricella, Stacey Gulde, Lori A. Anderson, Oleksandr Kalyuzhniy, Helen M. Neely, Jenni Ross, Thomas N. Earnest, Michael Soltis, Lori SchoenfeldFrank Zucker, Ethan A. Merritt, Erkang Fan, Christophe L M J Verlinde, Wim G J Hol

Research output: Contribution to journalArticlepeer-review

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)5939-5946
Number of pages8
JournalJournal of Medicinal Chemistry
Volume49
Issue number20
DOIs
StatePublished - Oct 5 2006
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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