Summary for 9H0S
| Entry DOI | 10.2210/pdb9h0s/pdb |
| Descriptor | Peptidyl-prolyl cis-trans isomerase F, mitochondrial, 1-[(4-aminophenyl)methyl]-3-[2-[2-(2-bromophenyl)pyrazolidin-1-yl]-2-oxidanylidene-ethyl]urea, 1,2-ETHANEDIOL, ... (8 entities in total) |
| Functional Keywords | peptidyl-prolyl cis-trans isomerase f, mitochondrial, isomerase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 19078.37 |
| Authors | Zacharchenko, T.,Lian, L.Y. (deposition date: 2024-10-08, release date: 2025-11-05, Last modification date: 2025-12-17) |
| Primary citation | Awais, M.,Woodley, C.M.,Guo, L.,Rogers, M.,Kershaw, N.,Zacharchenko, T.,Shore, E.,Kattakayam, A.,Mukherjee, R.,Criddle, D.N.,Leung, S.C.,Lee, H.,Burgess-McCann, J.,Luzyanin, K.,Berry, N.G.,Antonyuk, S.,Lian, L.Y.,Sutton, R.,O'Neill, P.M. Potent Preorganized Pyrazolidine Cyclophilin D Inhibitors Prevent Mitochondrial and Organ Injury in a Mouse Pancreatitis Disease Model. J.Med.Chem., 68:23910-23924, 2025 Cited by PubMed Abstract: Cyclophilin D inhibitors that prevent opening of the mitochondrial permeability transition pore (MPTP) are potential treatments for a range of acute and chronic diseases, including acute pancreatitis. Here, we report that replacement of carbon with nitrogen in the pyrrolidine headgroup of a series of cyclophilin D inhibitors gives a dramatic enhancement in binding affinity (>40 fold), and prolyl isomerase inhibition (PPIase) activity (>200 fold), which is ascribed to a preorganization of the pyrazolidine amide headgroup. Protein-ligand X-ray crystal structures and NMR and molecular modeling demonstrate the importance of -amide geometry within the preorganized conformation, ensuring the ligand headgroup is anchored in the S1' binding pocket, leading to potent nM PPIase inhibition and binding. Pyrazolidines potently inhibit MPTP opening and prevent pancreatic toxin-induced cell necrosis . , provided a significant improvement of acute pancreatitis biomarkers in the CER-AP mouse pancreatitis model, underlining the potential of this series. PubMed: 41208336DOI: 10.1021/acs.jmedchem.5c01146 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.45 Å) |
Structure validation
Download full validation report
