Inhibitors of Transketolase from Mycobacterium tuberculosis Targeted towards both the Diphosphate Binding Site and an Adjacent Hydrophobic Subsite

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Dmitry K. Nilov^1,2, Irina V. Gushchina³, Tatyana A. Shcherbakova¹, Simon M. Baldin^1,2, Vytas K. Švedas^2,3,a*

¹Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia

²Research Computing Center, Lomonosov Moscow State University, 119234 Moscow, Russia

³Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia

^* To whom correspondence should be addressed.

Received: September 26, 2024; Revised: December 4, 2024; Accepted: December 24, 2024

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Transketolase from Mycobacterium tuberculosis (mbTK) is involved in the pentose phosphate pathway essential for bacterial survival and thus constitutes an attractive target for the antituberculosis therapy. We found a new class of active site-targeted furan sulfonate inhibitors of mbTK that are capable of binding to both the thiamine diphosphate cofactor subsite and adjacent hydrophobic subsite Ile211-Leu402-Phe464, thereby suppressing enzyme activity. The most potent compound identified by computer screening, STK106769, was found to inhibit mbTK with IC₅₀ of 7 µM and suppress the growth of M. tuberculosis H37Rv strain. The hydrophobic subsite Ile211-Leu402-Phe464 of mbTK is substituted by significantly more polar residues in homologous human TK, which is an important factor determining the selectivity of binding of TK inhibitors.

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KEY WORDS: sulfonates, sulfo group, inhibitor, transketolase, mycobacteria, tuberculosis, molecular modeling, docking

DOI: 10.1134/S000629792460354X

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