Interactions between Human Glutamate Carboxypeptidase II and Urea-Based Inhibitors: Structural Characterization

被引：145

作者：

Barinka, Cyril ^{[1
]}

Byun, Youngjoo ^{[4
]}

Dusich, Crystal L. ^{[4
]}

Banerjee, Sangeeta R. ^{[4
]}

Chen, Ying ^{[4
]}

Castanares, Mark ^{[2
]}

Kozikowski, Alan P. ^{[3
]}

Mease, Ronnie C. ^{[4
]}

Pomper, Martin G. ^{[2
,4
]}

Lubkowski, Jacek ^{[1
]}

机构：

[1] NCI, Ctr Canc Res, Frederick, MD 21702 USA

[2] Johns Hopkins Med Inst, Dept Pharmacol & Mol Sci, Baltimore, MD 21231 USA

[3] Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA

[4] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21231 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 24期

关键词：

D O I：

10.1021/jm800765e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Urea-based, low molecular weight ligands of glutamate carboxypeptidase II (GCPII) have demonstrated efficacy in various models of neurological disorders and call serve as imaging agents for prostate cancer. To enhance further development of such compounds, we determined X-ray structures Of four complexes between human GCPII and urea-based inhibitors at high resolution. All ligands demonstrate in invariant glutarate moiety within the S1' pocket of the enzyme. The Ureido linkage between P1 and P1' inhibitor sites interacts with the active-site Zn-1(2+) ion and the side chains of Tyr552 and His553. Interactions within the S I pocket are defined primarily by a network of hydrogen bonds between the P1 carboxylate group of the inhibitors and the side chains of Arg534, Arg536, and Asn519. Importantly, we have identified a hydrophobic pocket accessory to the S1 site that call be exploited for structure-based design of novel GCPII inhibitors with increased lipophilicity.

引用

页码：7737 / 7743

页数：7

共 42 条

[41] NAAG peptidase inhibitor reduces acute neuronal degeneration and astrocyte damage following lateral fluid percussion TBI in rats [J].