Mymoona Akhter
Jamia Hamdard, India
Title: Computational design and validation of some novel, non-pteridine analogs as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors
Biography
Biography: Mymoona Akhter
Abstract
Dihydrofolate reductase (DHFR) is one of the validated drug targets in Mycobacterium tuberculosis infection. DHFR inhibitors have been used to treat various life threatening diseases such as cancer, malaria and several bacterial infections. However, all clinically effective DHFR inhibitors are non-selective and inhibit both human and pathogenic DHFR more or less to a similar extent. The crystal structures of DHFRs are validated and have been used for new drug design. Mycobacterium and human (h)-DHFRs show 26% structure similarity but their active sites are not identical and this information forms the basis of our study. Since most of the reported inhibitors of Mtb DHFR are pteridine based and are non-selective in nature therefore this study is aimed at to design and develop selective non-pteridine Mtb DHFR inhibitors. In the ternary complex of MTX with Mtb DHFR, in addition to MTX a glycerol “A” molecule is found in a depression nearby which shows interaction with the side-chains of Trp22, Asp27 and Gln28 which form a pocket in Mtb DHFR while glycerol is absent in h-DHFR. The h-DHFRs glycerol is absent and the site is packed with three hydrophobic residue side chains, Leu22, Pro26 and Phe31, which correspond to Leu20, Arg23 and Gln28 in Mtb DHFR. A compounds with side chain which could mimic the binding mode of glycerol to protein, may bind to Mtb DHFR selectively. Such a derivative should be sterically and chemically hindered from forming a complex with h-DHFR. This assumption forms the basis of present study and these understandings have been used for designing of selective inhibitors of Mtb DHFR. Number of novel non-pteridine based molecules has been identified through virtual screening of three databases. The synthesis of best hit has been carried out and tested for anti-tubercular activity. The results are promising and require further work in this direction