Identification of novel Mycobacterium tuberculosis dihydrofolate reductase inhibitors through rational drug design

Publication date: Available online 9 November 2016 Source:International Journal of Mycobacteriology Author(s): Mymoona Akhter 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 nonselective, and inhibit both human and pathogenic DHFRs more or less to a similar extent. The crystal structure of various DHFRs complexed with nicotinamide adenine dinucleotide phosphate and different inhibitors is available in the Protein Data Bank. The crystal structures are validated and have been used for new drug designing. M. tuberculosis DHFRs and human (h) DHFRs show 26% structure similarity, but their active sites are not identical and this characteristic forms the basis of this study. Because most of the reported inhibitors of M. tuberculosis DHFR are pteridine based and nonselective in nature, that is, they inhibit both microbial and host DHFRs, this study aimed to design and develop selective nonpteridine M. tuberculosis DHFR inhibitors. In the ternary complex of methotrexate with M. tuberculosis DHFR, whose structure is also available in the Protein Data Bank, the side of the aminopterin ring is accessible to the solvent; additionally, a glycerol “A” molecule is found in a depression nearby. This glycerol molecule interacts with the side c...
Source: International Journal of Mycobacteriology - Category: Infectious Diseases Source Type: research