9HTR

Structure of CypD in complex with an inhibitor.

This is a non-PDB format compatible entry.

Summary for 9HTR

• Entry DOI: 10.2210/pdb9htr/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase F, mitochondrial, 1-[(1~{S})-2-[2-(2-bromophenyl)pyrazolidin-1-yl]-2-oxidanylidene-1-phenyl-ethyl]-3-[[(1~{R},9~{R},10~{S})-10-oxidanyl-12-oxa-8-azatricyclo[7.3.1.0^{2,7}]trideca-2(7),3,5-trien-4-yl]methyl]urea (3 entities in total)
• Functional Keywords: n/a, isomerase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 18389.83

Authors

Zacharchenko, T.,Antonyuk, S.,Lian, L.Y. (deposition date: 2024-12-19, 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

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: 41208336
DOI: 10.1021/acs.jmedchem.5c01146

Experimental method

X-RAY DIFFRACTION (2.25 Å)