3KJS
Crystal Structure of T. cruzi DHFR-TS with 3 high affinity DHFR inhibitors: DQ1 inhibitor complex
Summary for 3KJS
| Entry DOI | 10.2210/pdb3kjs/pdb |
| Related | 2H2Q 3CL9 3CLB 3KJU 3KJW |
| Descriptor | Dihydrofolate reductase-thymidylate synthase, ethyl 4-(5-{[(2,4-diaminoquinazolin-6-yl)methyl]amino}-2-methoxyphenoxy)butanoate, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total) |
| Functional Keywords | oxidoreductase, transferase |
| Biological source | Trypanosoma cruzi |
| Total number of polymer chains | 4 |
| Total formula weight | 241867.23 |
| Authors | Schormann, N.,Senkovich, O.,Chattopadhyay, D. (deposition date: 2009-11-03, release date: 2010-06-09, Last modification date: 2023-09-06) |
| Primary citation | Schormann, N.,Velu, S.E.,Murugesan, S.,Senkovich, O.,Walker, K.,Chenna, B.C.,Shinkre, B.,Desai, A.,Chattopadhyay, D. Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase. Bioorg.Med.Chem., 18:4056-4066, 2010 Cited by PubMed 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. PubMed: 20452776DOI: 10.1016/j.bmc.2010.04.020 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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