Center for Theoretical Biological Physics, Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Bioorg Med Chem Lett. 2011 Dec 1;21(23):7064-7. doi: 10.1016/j.bmcl.2011.09.094. Epub 2011 Sep 29.
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 μM, and whole-cell minimum inhibitory concentrations of 20-200 μg/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.
结核分枝杆菌（Mtb）复杂且高度不透水的细胞壁在很大程度上使其能够抵抗化学治疗药物的作用。L-鼠李糖残基在 Mtb 细胞壁中占据重要的锚定位置，是新型抗结核药物的一个有吸引力的靶标。在这项工作中，我们报告了一项针对结核分枝杆菌 dTDP-脱氧-L-阿拉伯-4-己糖醛酸还原酶（RmlD）的虚拟筛选（VS）研究，RmlD 是 L-鼠李糖合成途径中的最后一种酶。通过两轮 VS，我们鉴定出四种 RmlD 抑制剂，其半抑制浓度为 0.9-25 μM，全细胞最小抑制浓度为 20-200 μg/ml。与我们之前针对另一种参与 L-鼠李糖合成的酶的高通量筛选相比，虚拟筛选的命中率更高，支持在未来的抗结核药物发现工作中使用计算方法。
