Structure-and-mechanism-based design and discovery of type II Mycobacterium tuberculosis dehydroquinate dehydratase inhibitors.
Mycobacterium tuberculosis is the causative agent of tuberculosis, a lethal infection disease that attacks the lungs. Now it becomes the major global health risk because of very long latent period, the persistent increase of new cases, and the emergence of multidrug-resistant and extensively drug-resistant strains. Therefore, there is an urgent need for the development of new, safe and more efficient tuberculosis drugs. The shikimate pathway has been considered as the attractive drug target due to its essentiality in algae, higher plants, bacteria, and fungi, but absence from mammals. In this review, we focus on the recent development of a wide variety of inhibitors of type II Mycobacterium tuberculosis dehydroquinate dehydratase, the third enzyme of this pathway. The structural and mechanistic features of the enzyme for the design and discovery of the inhibitors have been described. The key factors on the structure, binding, and affinity of the inhibitors have been also highlighted. This may direct the further development of type II Mycobacterium tuberculosis dehydroquinate dehydratase inhibitors as potent tuberculosis drugs.
Yuan
Y
Yao
Academy of Fundamental and Interdisciplinary Science, Harbin Institute of Technology 2 Yikuang Street, Harbin, PR China, 150080. yyuan@hit.edu.cn.
Ze-Sheng
ZS
Li
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
C431675:3-dehydroquinate dehydratase-shikimate - NADP oxidoreductase; D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D000429:Alcohol Oxidoreductases; D006836:Hydro-Lyases; C020000:3-dehydroquinate dehydratase