9LNH

Crystal structure of Peroxiredoxin I in complex with compound LC-PDin20

This is a non-PDB format compatible entry.

Summary for 9LNH

• Entry DOI: 10.2210/pdb9lnh/pdb
• Descriptor: Peroxiredoxin-1, (2~{S})-2-[[(2~{R},4~{a}~{S},6~{a}~{R},6~{a}~{S},14~{a}~{S},14~{b}~{R})-2,4~{a},6~{a},6~{a},9,14~{a}-hexamethyl-10-oxidanyl-11-oxidanylidene-1,3,4,5,6,13,14,14~{b}-octahydropicen-2-yl]carbamoylamino]butanoic acid (3 entities in total)
• Functional Keywords: celastrol derivative, prdx1 inhibitor, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 39224.86

Authors

Wang, Z.,Luo, C. (deposition date: 2025-01-21, release date: 2025-07-09)

Primary citation

Chen, S.,Wang, Z.,Gao, J.,Wang, Y.,Liang, J.,Zhu, Y.,Xu, H.,Chen, K.,Jin, L.,Zhang, H.,Xiong, H.,Luo, C.
Rapid Discovery of Celastrol Derivatives as Potent and Selective PRDX1 Inhibitors via Microplate-Based Parallel Compound Library and In Situ Screening.
J.Med.Chem., 2025

PubMed Abstract: Celastrol has been identified as a reactive oxygen species (ROS) elevator that reduces cancer cell proliferation by inhibiting peroxiredoxin (PRDX) activity, albeit with poor selectivity. We describe a semiautomated and microplate-based parallel compound library approach leading to the rapid discovery of celastrol derivatives that are potent and selective PRDX1 inhibitors. Amide coupling and the urea bond forming reactions were used to construct a 2720-member celastrol derivative library, followed by PRDX1 enzyme inhibition assay screening, leading to the rapid identification of a series of celastrol derivatives demonstrating promising PRDX1 inhibition activity. Compound displayed the best anti-PRDX1 activity (IC = 0.042 μM) with selectivity toward the PRDX family, as well as good antiproliferative activity against colorectal cancer cells. A cocrystal structure of PRDX1 with and molecular docking studies provided insight into the binding mode of the inhibitors with PRDX1, aiding in the structure-based design of future PRDX1 inhibitors.

PubMed: 40546088
DOI: 10.1021/acs.jmedchem.5c00433

Experimental method

X-RAY DIFFRACTION (1.63 Å)