Abstract
The worldwide TB structural genomics initiative has identified several new drug targets for Mycobacterium tuberculosis (M. tb). Dihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate that is essential for DNA synthesis. Inhibition of its activity leads to arrest of DNA synthesis and hence cell death. Thus, M. tb DHFR (mtDHFR) is an attractive novel drug target for developing anti-TB drugs. Structural comparison of mtDHFR and human DHFR (hDHFR) reveals key differences in the active sites. These differences can be exploited for the design of selective inhibitors for mtDHFR. Based on the recently determined high resolution crystal structure of mtDHFR complexed with known inhibitor methotrexate (MTX) and cofactor NADPH, a tri-peptide inhibitor has been identified using a structure-based drug design approach. Docking studies indicate that the designed tripeptide inhibitor has a high potency (K
d = 1.78 nM) and is a selective (approximately 120 fold over hDHFR) inhibitor for mtDHFR. Hence, the tripeptide is a suitable lead compound for the development of novel anti-TB drugs.
