Novel inhibitors ofMycobacterium tuberculosisdTDP-6-deoxy-l-lyxo-4-hexulose reductase (RmlD) identified by virtual screening

Yi Wang, Tamara Noelle Hess, Victoria Jones, Joe Zhongxiang Zhou, Michael R. McNeil, J. Andrew McCammon

Index: Bioorg. Med. Chem. Lett. 21 , 7064-7, (2011)

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Abstract

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.Copyright © 2011 Elsevier Ltd. All rights reserved.