Title of article :
Identification of triazinoindol-benzimidazolones as nanomolar inhibitors of the Mycobacterium tuberculosis enzyme TDP-6-deoxy-d-xylo-4-hexopyranosid-4-ulose 3,5-epimerase (RmlC) Original Research Article
Author/Authors :
Sharmila Sivendran، نويسنده , , Victoria Jones، نويسنده , , Dianqing Sun، نويسنده , , Yi Wang، نويسنده , , Anna E. Grzegorzewicz، نويسنده , , Michael S. Scherman، نويسنده , , Andrew D. Napper، نويسنده , , J. Andrew McCammon، نويسنده , , Richard E. Lee and Stephen W. White، نويسنده , , Scott L. Diamond، نويسنده , , Michael McNeil، نويسنده ,
Abstract :
High-throughput screening of 201,368 compounds revealed that 1-(3-(5-ethyl-5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)propyl)-1H-benzo[d]imidazol-2(3H)-one (SID 7975595) inhibited RmlC a TB cell wall biosynthetic enzyme. SID 7975595 acts as a competitive inhibitor of the enzyme’s substrate and inhibits RmlC as a fast-on rate, fully reversible inhibitor. An analog of SID 7975595 had a Ki of 62 nM. Computer modeling showed that the binding of the tethered two-ringed system into the active site occurred at the thymidine binding region for one ring system and the sugar region for the other ring system.
Keywords :
RmlC inhibitor , TB cell wall , Tuberculosis , TB drug discovery
