ИСТИНА

Transketolase (TK) from Mycobacterium tuberculosis is involved in the pentose phosphate pathway essential for the bacterial survival and thus constitutes an attractive target for antituberculosis therapy. However, to our knowledge, no potent and selective inhibitors of this enzyme have been reported to date. Bioinformatics analysis allowed us to identify an important hydrophobic site in the structure of the mycobacterial enzyme formed by Ile211, Leu402, and Phe464 that corresponds to a significantly more polar site in the human TK and may serve as a selectivity determining factor at binding of TK inhibitors. As this hydrophobic site is adjacent to the pyrophosphate binding site, the following criteria have been considered to design efficient inhibitors: i) strong interaction with the thiamine pyrophosphate binding site mediated by a phosphate group isostere (e.g., a sulfo group); ii) favorable contacts with the hydrophobic site residues Ile211-Leu402-Phe464. Virtual screening against the mycobacterial TK model was performed among sulfonates from the Vitas-M library using Lead Finder (http://moltech.ru). The most promising compounds selected by their ability to form the abovementioned interactions were shown to suppress the activity of purified TKs from Saccharomyces cerevisiae and M. tuberculosis in the micromolar concentration range, but exerted no effect against human enzyme. The yeast enzyme was demonstrated to be a convenient experimental model for screening inhibitors of mycobacterial TK due to their high structural similarity. The most potent compound was found to inhibit TK from M. tuberculosis with the IC50 value of 100 µM and effectively suppress the growth of a virulent mycobacterial strain H37Rv.