Novel inhibitors of Mycobacterium tuberculosis dTDP-6-deoxy-L-lyxo-4-hexulose reductase (RmlD) identified by virtual screening

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Wang, Yi^2,3  Hess, Tamara Noelle¹  Jones, Victoria¹  Zhou, Joe Zhongxiang^2,3  McNeil, Michael R.¹  McCammon, J. Andrew^2,3 

[1] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA

[2] Univ Calif San Diego, Howard Hughes Med Inst, Dept Chem & Biochem, Ctr Theoret Biol Phys, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Howard Hughes Med Inst, Dept Pharmacol, Ctr Theoret Biol Phys, La Jolla, CA 92093 USA

关键词: RmlD;    M. tuberculosis;    Virtual screening;    L-Rhamnose synthesis;    Anti-tuberculsois;    Computer-aided drug design;   

DOI  :  10.1016/j.bmcl.2011.09.094

来源: Elsevier

【 摘 要 】

The complex and highly impermeable cell wall of Mycobacterium tuberculosis (Mtb) is largely responsible for the ability of the mycobacterium to resist the action of chemical therapeutics. An L-rhamnosyl residue, which occupies an important anchoring position in the Mtb cell wall, is an attractive target for novel anti-tuberculosis drugs. In this work, we report a virtual screening (VS) study targeting Mtb dTDP-deoxy-L-lyxo-4-hexulose reductase (RmlD), the last enzyme in the L-rhamnosyl synthesis pathway. Through two rounds of VS, we have identified four RmlD inhibitors with half inhibitory concentrations of 0.9-25 mu M, and whole-cell minimum inhibitory concentrations of 20-200 mu g/ml. Compared with our previous high throughput screening targeting another enzyme involved in L-rhamnosyl synthesis, virtual screening produced higher hit rates, supporting the use of computational methods in future anti-tuberculosis drug discovery efforts. (C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

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