8VK6
14alpha-demethylase (CYP51) with amide-linked long arm extension antifungal azole inhibitor
This is a non-PDB format compatible entry.
Summary for 8VK6
| Entry DOI | 10.2210/pdb8vk6/pdb |
| Descriptor | Lanosterol 14-alpha demethylase, PROTOPORPHYRIN IX CONTAINING FE, N-[(2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4'-(trifluoromethoxy)[1,1'-biphenyl]-4-carboxamide, ... (6 entities in total) |
| Functional Keywords | amide-linked azole inhibitor, cyp51, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Saccharomyces cerevisiae YJM789 (Baker's yeast) |
| Total number of polymer chains | 1 |
| Total formula weight | 63769.03 |
| Authors | Tyndall, J.D.A.,Monk, B.C.,Simons, C. (deposition date: 2024-01-08, release date: 2025-01-15, Last modification date: 2025-07-30) |
| Primary citation | Alsulaimany, M.,Keniya, M.V.,Alanazi, R.S.,N Ruma, Y.,Hughes, C.S.,Jones, A.T.,Tyndall, J.D.A.,Parker, J.E.,Monk, B.C.,Simons, C. Exploring Long Arm Amide-Linked Side Chains in the Design of Antifungal Azole Inhibitors of Sterol 14 alpha-Demethylase (CYP51). J.Med.Chem., 68:10781-10799, 2025 Cited by PubMed Abstract: The rise in fungal drug resistance has exacerbated the treatment of invasive fungal infections, most commonly caused by . This research describes the synthesis of extended "long-arm" azole antifungals that were evaluated against wild-type and resistant fungal species. Biphenyl derivative was the most effective derivative, displaying potent inhibitory activity against , , and CYP51 enzymes, including in resistant strains, in comparison with posaconazole. The X-ray crystal structure of - complexed with CYP51 showed a hydrogen bond between the oxygen of the trifluoromethoxy group of and the His381 side chain of CYP51, which is postulated to contribute significantly to its binding, and stabilization in the presence of the CYP51 Y140F/H, and CYP51 Y132F mutations and the K143R mutation. Computational studies and IC evaluation of compound vs wild-type, Y132F, and Y132H/K143 mutant strains supported MIC observations. PubMed: 40403151DOI: 10.1021/acs.jmedchem.4c02922 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.89 Å) |
Structure validation
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