title: Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase.
abstract: Dihydrofolate reductase (DHFR) of the parasite Trypanosoma cruzi (T. cruzi) is a potential target for developing drugs to treat Chagas' disease. We have undertaken a detailed structure-activity study of this enzyme. We report here synthesis and characterization of six potent inhibitors of the parasitic enzyme. Inhibitory activity of each compound was determined against T. cruzi and human DHFR. One of these compounds, ethyl 4-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)butanoate (6b) was co-crystallized with the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of T. cruzi and the crystal structure of the ternary enzyme:cofactor:inhibitor complex was determined. Molecular docking was used to analyze the potential interactions of all inhibitors with T. cruzi DHFR and human DHFR. Inhibitory activities of these compounds are discussed in the light of enzyme-ligand interactions. Binding affinities of each inhibitor for the respective enzymes were calculated based on the experimental or docked binding mode. An estimated 60-70% of the total binding energy is contributed by the 2,4-diaminoquinazoline scaffold.
authors.affiliation: Department of Medicine, University of Alabama, Birmingham, Birmingham, AL 35294, USA.
authors.forename: Norbert
authors.initials: N
authors.lastname: Schormann
authors.forename: Sadanandan E
authors.initials: SE
authors.lastname: Velu
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Murugesan
authors.forename: Olga
authors.initials: O
authors.lastname: Senkovich
authors.forename: Kiera
authors.initials: K
authors.lastname: Walker
authors.forename: Bala C
authors.initials: BC
authors.lastname: Chenna
authors.forename: Bidhan
authors.initials: B
authors.lastname: Shinkre
authors.forename: Amar
authors.initials: A
authors.lastname: Desai
authors.forename: Debasish
authors.initials: D
authors.lastname: Chattopadhyay
mesh_terms: D014355:Chagas Disease / Q000188:drug therapy; D003198:Computer Simulation; D003460:Crystallization; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D011485:Protein Binding; D011799:Quinazolines; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011799:Quinazolines; D014344:Trypanocidal Agents; D013762:Tetrahydrofolate Dehydrogenase