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Structure-Based Design of DevR Inhibitor Active against Nonreplicating Mycobacterium tuberculosis

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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Official URL: http://pubs.acs.org/doi/abs/10.1021/jm900358q


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
Publication: Journal of medicinal chemistry
Publisher: American Chemical Society
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
URI: http://eprints.iisc.ac.in/id/eprint/24822

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