screening the maybridge rule of 3 fragment library for compounds that interact with the trypanosoma brucei myo-inositol-3-phosphate synthase andor show trypanocidal activity英文论文.pdfVIP

SAGE-Hindawi Access to Research Molecular Biology International Volume 2011, Article ID 389364, 14 pages doi:10.4061/2011/389364 Research Article Screening the MayBridge Rule of 3 Fragment Library for Compounds That Interact with the Trypanosoma brucei myo -Inositol-3-Phosphate Synthase and/or Show Trypanocidal Activity Louise L. Major and Terry K. Smith Biomolecular Science, The North Haugh, The University of St. Andrews, Fife, Scotland, KY16 9ST, UK Correspondence should be addressed to Terry K. Smith, tks1@st-andrews.ac.uk Received 31 December 2010; Revised 23 February 2011; Accepted 23 February 2011 Academic Editor: Wanderley De Souza Copyright © 2011 L. L. Major and T. K. Smith. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Inositol-3-phosphate synthase (INO1) has previously been genetically validated as a drug target against Trypanosoma brucei, the causative agent of African sleeping sickness. Chemical intervention of this essential enzyme could lead to new therapeutic agents. Unfortunately, no potent inhibitors of INO1 from any organism have been reported, so a screen for potential novel inhibitors of T. brucei INO1was undertaken. Detection of inhibition of T. brucei INO1 is problematic due to the nature of the reaction. Direct detection requires differentiation between glucose-6-phosphate and inositol-3-phosphate. Coupled enzyme assays could give false positives as potentially they could inhibit the coupling enzyme. Thus, an alternative approach of differential scanning fluorimetry to identify compounds that interact with T. brucei INO1 was employed to screen ∼670 compounds from the MayBridge Rule of