9JFM

Co-crystal Structure of sEH with tetrahydroberberine derivative

This is a non-PDB format compatible entry.

Summary for 9JFM

• Entry DOI: 10.2210/pdb9jfm/pdb
• Descriptor: Bifunctional epoxide hydrolase 2, MAGNESIUM ION, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: complex, small molecule, tetrahydroberberine derivative, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 63332.43

Authors

Wang, H.,Feng, Y.,Du, X.Y. (deposition date: 2024-09-04, release date: 2025-09-10, Last modification date: 2026-04-01)

Primary citation

Liu, X.Z.,Du, X.Y.,Xie, W.S.,Ding, J.,Zhu, M.Z.,Feng, Z.Q.,Wang, H.,Feng, Y.,Yu, M.J.,Liu, S.M.,Liu, W.T.,Zhu, X.H.,Liang, J.H.
Redesigning Berberines and Sanguinarines to Target Soluble Epoxide Hydrolase for Enhanced Anti-Inflammatory Efficacy.
J.Med.Chem., 67:22168-22190, 2024

PubMed Abstract: Amino-berberine has remained underexplored due to limited biological evaluation and total synthesis approaches. In inflammation therapy, soluble Epoxide Hydrolase (sEH) is a promising target, yet natural scaffolds remain underutilized. Our study advances the field by redesigning natural compounds─berberine and sanguinarine─with strategic urea modifications and hydrogenated frameworks, creating novel sEH inhibitors with enhanced efficacy. Through total synthesis and structure-activity relationship studies of amino-berberine derivatives, chiral tetrahydroberberine (coded ) emerged as the most potent lead, with an IC value of 1.20 nM. showed reduced CYP enzyme impact, potent therapeutic effects on acute pancreatitis, no acute toxicity, and superior pharmacokinetic properties, with an oral bioavailability of 89.3%. Structural insights from crystallography of bound to sEH revealed key interactions: three with the tetrahydroberberine framework and three hydrogen bonds with the urea group, highlighting as a novel lead for sEH-targeted therapies in inflammation.

PubMed: 39658523
DOI: 10.1021/acs.jmedchem.4c02202

Experimental method

X-RAY DIFFRACTION (3.13 Å)