Nad+ dependent dna ligase (rv3014c) from M. tuberculosis: strategies for inhibitor design

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 co-factor NAD+. Recently we identified that the BRCT-domain is essential for the enzyme activity of MtuLigA. We 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 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.