4H6O
Sterol 14-alpha demethylase (CYP51)from Trypanosoma cruzi in complex with the inhibitor NEU321 (1-(3-(4-chloro-3,5-dimethylphenoxy)benzyl)-1H-imidazole
Summary for 4H6O
| Entry DOI | 10.2210/pdb4h6o/pdb |
| Related | 3k1o 3ksw |
| Descriptor | Sterol 14-alpha demethylase, PROTOPORPHYRIN IX CONTAINING FE, 1-[3-(4-chloro-3,5-dimethylphenoxy)benzyl]-1H-imidazole, ... (4 entities in total) |
| Functional Keywords | sterol 14-alpha demethylase (cyp51), cytochrome p450, heme, oxidoreductase, monooxygenase, sterol biosynthesis, eukaryotic membranes, cytochrome p450 fold, endoplasmic reticulum membrane, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Trypanosoma cruzi |
| Cellular location | Membrane ; Single-pass membrane protein : Q7Z1V1 |
| Total number of polymer chains | 1 |
| Total formula weight | 53613.38 |
| Authors | Wawrzak, Z.,Hargrove, T.Y.,Pollastri, M.P.,Lepesheva, G.I. (deposition date: 2012-09-19, release date: 2013-03-20, Last modification date: 2023-09-20) |
| Primary citation | Andriani, G.,Amata, E.,Beatty, J.,Clements, Z.,Coffey, B.J.,Courtemanche, G.,Devine, W.,Erath, J.,Juda, C.E.,Wawrzak, Z.,Wood, J.T.,Lepesheva, G.I.,Rodriguez, A.,Pollastri, M.P. Antitrypanosomal Lead Discovery: Identification of a Ligand-Efficient Inhibitor of Trypanosoma cruzi CYP51 and Parasite Growth. J.Med.Chem., 56:2556-2567, 2013 Cited by PubMed Abstract: Chagas disease is caused by the intracellular protozoan parasite Trypanosomal cruzi , and current drugs are lacking in terms of desired safety and efficacy profiles. Following on a recently reported high-throughput screening campaign, we have explored initial structure-activity relationships around a class of imidazole-based compounds. This profiling has uncovered compounds 4c (NEU321) and 4j (NEU704), which are potent against in vitro cultures of T. cruzi and are greater than 160-fold selective over host cells. We report in vitro drug metabolism and properties profiling of 4c and show that this chemotype inhibits the T. cruzi CYP51 enzyme, an observation confirmed by X-ray crystallographic analysis. We compare the binding orientation of 4c to that of other, previously reported inhibitors. We show that 4c displays a significantly better ligand efficiency and a shorter synthetic route over previously disclosed CYP51 inhibitors, and should therefore be considered a promising lead compound for further optimization. PubMed: 23448316DOI: 10.1021/jm400012e PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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