An Improved Model of the Trypanosoma brucei CTP Synthetase Glutaminase Domain–Acivicin Complex

• Published in: ChemMedChem 2017-04, Vol.12 (8), p.577-579
• Main Authors: Oliveira de Souza, Juliana, Dawson, Alice, Hunter, William N.
• Format: Article
• Language: English
• Subjects: acivicin; Bacillus subtilis - enzymology; Carbon-Nitrogen Ligases - antagonists & inhibitors; Carbon-Nitrogen Ligases - chemistry; Catalytic Domain; Communication; Communications; CTP synthetase; gamma-Glutamyltransferase - chemistry; glutaminase; Glutaminase - antagonists & inhibitors; Glutaminase - chemistry; Helicobacter pylori - enzymology; Hydrogen Bonding; Isoxazoles - chemistry; Isoxazoles - pharmacology; Ligands; structure-based drug discovery; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei; Trypanosoma brucei brucei - enzymology; trypanosomiasis
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201700118

The natural product acivicin inhibits the glutaminase activity of cytidine triphosphate (CTP) synthetase and is a potent lead compound for drug discovery in the area of neglected tropical diseases, specifically trypanosomaisis. A 2.1‐Å‐resolution crystal structure of the acivicin adduct with the glutaminase domain from Trypanosoma brucei CTP synthetase has been deposited in the RCSB Protein Data Bank (PDB) and provides a template for structure‐based approaches to design new inhibitors. However, our assessment of that data identified deficiencies in the model. We now report an improved and corrected inhibitor structure with changes to the chirality at one position, the orientation and covalent structure of the isoxazoline moiety, and the location of a chloride ion in an oxyanion binding site that is exploited during catalysis. The model is now in agreement with established chemical principles and allows an accurate description of molecular recognition of the ligand and the mode of binding in a potentially valuable drug target. Straightened out: The contribution of structural data to medicinal chemistry is well recognized. However, the warning “user beware” applies. With an interest in African trypanosomiasis, we noted errors in the Trypanosoma brucei CTP synthetase glutaminase domain–acivicin complex. We corrected the chirality and covalent structure of the isoxazoline moiety and identified a chloride ion in an oxyanion binding site. The new model agrees with established chemical principles and provides an accurate description of molecular recognition in a potentially valuable drug target.