Gupta, Rajesh Kumar and Thakur, Tejender S and Desiraju, Gautam R and Tyagi, Jaya Sivaswami (2009) Structure-Based Design of DevR Inhibitor Active against Nonreplicating Mycobacterium tuberculosis. In: Journal of medicinal chemistry, 52 (20). pp. 6324-6334.
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Antitubercular treatment is directed against actively replicating organisms. There is an urgent need to develop drugs targeting persistent subpopulations of Mycobacterium tuberculosis. The DevR response regulator is believed to play a key role in bacterial dormancy adaptation during hypoxia. We developed a homology-based model of DevR and used it for the rational design of inhibitors. A phenylcoumarin derivative (compound 10) identified by in silico pharmacophore-based screening of 2.5 million compounds employing protocols with some novel features including a water-based pharmacophore query, was characterized further. Compound 10 inhibited DevR binding to target DNA, down-regulated dormancy genes transcription, and drastically reduced survival of hypoxic but not nutrient-starved dormant bacteria or actively growing organ ` isms. Our findings suggest that compound 10 ``locks'' DevR in an inactive conformation that is unable to bind cognate DNA and induce the dormancy regulon. These results provide proof-of-concept for DevR as a novel target to develop molecules with sterilizing activity against tubercle bacilli.
|Item Type:||Journal Article|
|Additional Information:||Copyright for this article belongs to American Chemical Society.|
|Department/Centre:||Division of Chemical Sciences > Solid State & Structural Chemistry Unit|
|Date Deposited:||07 Jan 2010 06:34|
|Last Modified:||19 Sep 2010 05:52|
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