Authors

Discussion

Tuberculosis is an infectious disease that affects millions of population every year. Mtb DHFR is a validated target that is vital for nucleic acids biosynthesis and therefore DNA formation and cell replication. There are no selective Mtb DHFR inhibitors available against this target till date.

What the specific objectives of my work are

To identify novel Mtb DHFR inhibitors through molecular modelling and virtual screening of various public domain and in-house databases. Synthesis of selected hits and their analogues and their anti-tubercular activity

A brief explanation of the methods I have used

Mtb DHFR contains 159 amino acid residues compared with 187 for the human DHFR with active site on C-terminal side of the sheet. Structural comparison of these complexes revealed that there is 74% similarity between the proteins, such a high similarity the active site environments of the two proteins from host and pathogen contain interesting differences. We have performed virtual screening against Mtb DHFR and h DHFR by taking public domain and in house databases and selection of molecules has been done on the basis of selective binding interaction to Mtb DHFR. The hits identified (17) were synthesized in lab and characterized by ¹H NMR, LCMS and IR. The compounds were screened for their antitubercular activity at TAACF, NIAD USA.

A succinct statement of the results and my conclusions:

The main objective of the present study was to identify the drug like molecules as selective inhibitors for Mtb DHFR by using Virtual Screening. The compounds were found to have inhibitory activity in range of (30- 100) μM. All compounds presented low cytotoxici