Novel inhibitors of Mycobacterium tuberculosis dTDP-6-deoxy-L-lyxo-4-hexulose reductase (RmlD) identified by virtual screening.
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.
Center for Theoretical Biological Physics, Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Yi
Y
Wang
Tamara Noelle
TN
Hess
Victoria
V
Jones
Joe Zhongxiang
JZ
Zhou
Michael R
MR
McNeil
J
J
Andrew McCammon
D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D013401:Sugar Alcohol Dehydrogenases; C405941:thymidine diphosphate-6-deoxy-L-lyxo-4-hexulose reductase