Pharmacophore Modeling and Virtual Screening for Novel Acidic Inhibitors of Microsomal Prostaglandin E2 Synthase-1 (mPGES-1)

被引：48

作者：

Waltenberger, Birgit ^{[1
,2
]}

Wiechmann, Katja ^{[3
]}

Bauer, Julia ^{[3
]}

Markt, Patrick ^{[1
,2
]}

Noha, Stefan M. ^{[1
,2
]}

Wolber, Gerhard ^{[1
,2
,5
]}

Rollinger, Judith M. ^{[1
,2
]}

Werz, Oliver ^{[3
,4
]}

Schuster, Daniela ^{[1
,2
]}

Stuppner, Hermann ^{[1
,2
]}

机构：

[1] Univ Innsbruck, Inst Pharm, A-6020 Innsbruck, Austria

[2] Univ Innsbruck, CMBI, A-6020 Innsbruck, Austria

[3] Univ Tubingen, Inst Pharmaceut, Dept Pharmaceut Analyt, D-72076 Tubingen, Germany

[4] Univ Jena, Inst Pharm, Chair Pharmaceut Med Chem, D-07743 Jena, Germany

[5] Free Univ Berlin, Dept Pharmaceut Chem, Inst Pharm, D-14195 Berlin, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 09期

基金：

奥地利科学基金会;

关键词：

5-LIPOXYGENASE; INFLAMMATION; 3D-QSAR; CANCER; CELLS;

D O I：

10.1021/jm101309g

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Microsomal prostaglandin E-2 synthase-1 (mPGES-1) catalyzes prostaglandin E-2 formation and is considered as a potential anti-inflammatory pharmacological target. To identify novel chemical scaffolds active on this enzyme, two pharmacophore models for acidic mPGES-1 inhibitors were developed and theoretically validated using information on mPGES-1 inhibitors from literature. The models were used to screen chemical databases supplied from the National Cancer Institute (NCI) and the Specs. Out of 29 compounds selected for biological evaluation, nine chemically diverse compounds caused concentration-dependent inhibition of mPGES-1 activity in a cell-free assay with IC50 values between 0.4 and 7.9 mu M, respectively. Further pharmacological characterization revealed that also 5-lipoxygenase (5-LO) was inhibited by most of these active compounds in cell-free and cell-based assays with IC50 values in the low micromolar range. Together, nine novel chemical scaffolds inhibiting mPGES-1 are presented that may possess anti-inflammatory properties based on the interference with eicosanoid biosynthesis.

引用

页码：3163 / 3174

页数：12

共 29 条

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