8ZBL

Glycosidated glycyrrhetinic acid derivative as a soluble epoxide hydrolase inhibitor

This is a non-PDB format compatible entry.

Summary for 8ZBL

• Entry DOI: 10.2210/pdb8zbl/pdb
• Descriptor: Bifunctional epoxide hydrolase 2, 1-[[(2~{S},4~{a}~{S},6~{a}~{R},6~{a}~{S},6~{b}~{R},8~{a}~{R},10~{S},12~{a}~{S},14~{b}~{S})-10-[(2~{S},3~{S},4~{S},5~{S},6~{R})-6-(hydroxymethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-2,4~{a},6~{a},6~{b},9,9,12~{a}-heptamethyl-13-oxidanylidene-3,4,5,6,6~{a},7,8,8~{a},10,11,12,14~{b}-dodecahydro-1~{H}-picen-2-yl]methyl]-3-(oxan-4-ylmethyl)urea, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: inhibition, complex, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 63563.92

Authors

Wang, H.,Feng, Y.,Ge, Z.H. (deposition date: 2024-04-26, release date: 2024-12-11)

Primary citation

Liu, Q.,Wang, Y.X.,Ge, Z.H.,Zhu, M.Z.,Ding, J.,Wang, H.,Liu, S.M.,Liu, R.C.,Li, C.,Yu, M.J.,Feng, Y.,Zhu, X.H.,Liang, J.H.
Discovery of glycosidated glycyrrhetinic acid derivatives: Natural product-based soluble epoxide hydrolase inhibitors.
Eur.J.Med.Chem., 280:116937-116937, 2024

PubMed Abstract: There are few reports on soluble epoxide hydrolase (sEH) structure-activity relationship studies using natural product-based scaffolds. In this study, we discovered that C-30 urea derivatives of glycyrrhetinic acid such as 33, rather than C-20/C-3 urea derivatives, possess in vitro sEH inhibitory capabilities. Furthermore, we explored the impact of stereoconfigurations at C-3 and C-18 positions, and glycosidic bonds at the 3-OH on the compound's activity. Consequently, a glycoside of 33, specifically 49Cα containing alpha-oriented mannose, exhibited promising in vivo efficacy in alleviating carrageenan-induced paw edema and acetic acid-induced writhing. Meanwhile, 49Cα demonstrated potential in mitigating acute pancreatitis by modulating the ratios of anti-inflammatory epoxyeicosatrienoic acids (EETs) to pro-inflammatory dihydroxyeicosatrienoic acids (DHETs). The co-crystal structure of sEH in complex with 49Cα revealed that the N-tetrahydropyranylmethylene urea hydrogen bonded with the residues within the sEH tunnel, contrasting with the mannose component that extended beyond the tunnel's confines. Our findings highlight 49Cα (coded LQ-38) as a promising candidate for anti-inflammatory and analgesic effects, and pave the way for the future rational design of triterpenoid-based sEH inhibitors.

PubMed: 39413443
DOI: 10.1016/j.ejmech.2024.116937

Experimental method

X-RAY DIFFRACTION (2.7 Å)