Abstract
NAD+-dependent DNA ligases (LigA) are essential enzymes found only in bacteria and some virus species. This makes them attractive drug targets. Based on the crystal structure of the NAD+ binding domain of the M. tuberculosis enzyme (MtuLigA) and virtual screening, we have earlier identified several novel classes of inhibitors for this enzyme. These inhibitors bind to the adenylation domain and compete with the cofactor NAD+. Recently, we identified that the BRCT domain is essential for the enzyme activity of MtuLigA. We have used virtual screening to identify compounds from the CAP database that should potentially bind to the BRCT domain. These will now be evaluated as inhibitors of the enzyme with a novel mechanism of action. Challenges faced in designing specific and potent inhibitors of the enzyme which can distinguish between the human adenosine triphosphate (ATP)-dependent ligase and MtuLigA are additionally discussed in this report. Proposed strategies for the design of potent inhibitors with desired properties are also outlined.
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Acknowledgements
The work was funded by the Council of Scientific and Industrial Research, India grant CMM0017 and SMM0003. DD, VK, and SKS acknowledge fellowships from CSIR. This is communication number 7135 from CDRI.
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Dube, D., Kukshal, V., Srivastava, S.K. et al. NAD+-dependent DNA ligase (Rv3014c) from M. tuberculosis: Strategies for inhibitor design. Med Chem Res 17, 189–198 (2008). https://doi.org/10.1007/s00044-007-9052-5
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DOI: https://doi.org/10.1007/s00044-007-9052-5