Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methy1-4-phenylisoxazole (P6)

被引：73

作者：

Cingolani, Gino ^{[1
,2
]}

Panella, Andrea ^{[3
]}

Perrone, Maria Grazia ^{[3
]}

Vitale, Paola ^{[3
]}

Di Mauro, Giuseppe ^{[4
]}

Fortuna, Cosimo G. ^{[4
]}

Armen, Roger S. ^{[5
]}

Ferorelli, Savina ^{[3
]}

Smith, William L. ^{[6
]}

Scilimati, Antonio ^{[3
]}

机构：

[1] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA

[2] CNR, Inst Biomembranes & Bioenerget, Via Amendola 165-A, I-70125 Bari, Italy

[3] Univ Bari Aldo Moro, Dept Pharm Pharmaceut Sci, Via E Orabona 4, I-70125 Bari, Italy

[4] Univ Catania, Dept Sci Chim, Viale Andrea Doria 6, I-95125 Catania, Italy

[5] Thomas Jefferson Univ, Dept Pharmaceut Sci, Coll Pharm, Philadelphia, PA 19107 USA

[6] Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 138卷

关键词：

Cyclooxygenase-1; inhibition; Mofezolac; P6; Diarylisoxazole; X-ray crystallography; Molecular modelling; CRYSTAL-STRUCTURE; SYNTHASE-1; DESIGN; SITE;

D O I：

10.1016/j.ejmech.2017.06.045

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The diarylisoxazole molecular scaffold is found in several NSAIDs, especially those with high selectivity for COX-1. Here, we have determined the structural basis for COX-1 binding to two diarylisoxazoles: mofezolac, which is polar and ionizable, and 3-(5-chlorofuran-2-y1)-5-methyl-4-phenylisoxazole (P6) that has very low polarity. X-ray analysis of the crystal structures of COX-1 bound to mofezolac and 3-(5chlorofuran-2-yl)-5-methyl-4-phenylisoxazole allowed the identification of specific binding determinants within the enzyme active site, relevant to generate structure/activity relationships for diarylisoxazole NSAIDs. (C) 2017 Elsevier Masson SAS. All rights reserved.

引用

页码：661 / 668

页数：8

共 40 条

[1] PHENIX:: building new software for automated crystallographic structure determination [J].

Adams, PD ;

Grosse-Kunstleve, RW ;

Hung, LW ;

Ioerger, TR ;

McCoy, AJ ;

Moriarty, NW ;

Read, RJ ;

Sacchettini, JC ;

Sauter, NK ;

Terwilliger, TC .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2002, 58 :1948-1954

[2]

Baigent C, 2002, BMJ-BRIT MED J, V324, P71, DOI 10.1136/bmj.324.7329.71

[3] A common reference framework for analyzing/comparing proteins and ligands. Fingerprints for ligands and proteins (FLAP): Theory and application [J].

Baroni, Massimo ;

Cruciani, Gabriele ;

Sciabola, Simone ;

Perruccio, Francesca ;

Mason, Jonathan S. .

JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2007, 47 (02) :279-294

[4] Highly Selective Cyclooxygenase-1 Inhibitors P6 and Mofezolac Counteract Inflammatory State both In Vitro and In Vivo Models of Neuroinflammation [J].

Calvello, Rosa ;

Lofrumento, Dario Domenico ;

Perrone, Maria Grazia ;

Cianciulli, Antonia ;

Salvatore, Rosaria ;

Vitale, Paola ;

De Nuccio, Francesco ;

Giannotti, Laura ;

Nicolardi, Giuseppe ;

Panaro, Maria Antonietta ;

Scilimati, Antonio .

FRONTIERS IN NEUROLOGY, 2017, 8

[5]

DeLano WL., 2002, PYMOL MOL GRAPHICS S

[6] Novel synthesis of 3,4-diarylisoxazole analogues of valdecoxib: Reversal cyclooxygenase-2 selectivity by sulfonamide group removal [J].

Di Nunno, L ;

Vitale, P ;

Scilimati, A ;

Tacconelli, S ;

Patrignani, P .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (20) :4881-4890

[7] Coot:: model-building tools for molecular graphics [J].

Emsley, P ;

Cowtan, K .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 :2126-2132

[8] Analgesic effect of mofezolac, a non-steroidal anti-inflammatory drug, against phenylquinone-induced acute pain in mice [J].

Goto, K ;

Ochi, H ;

Yasunaga, Y ;

Matsuyuki, H ;

Imayoshi, T ;

Kusuhara, H ;

Okumoto, T .

PROSTAGLANDINS & OTHER LIPID MEDIATORS, 1998, 56 (04) :245-254

[9] Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities [J].

Grosser, T ;

Fries, S ;

FitzGerald, GA .

JOURNAL OF CLINICAL INVESTIGATION, 2006, 116 (01) :4-15

[10] The 2.0 A resolution crystal structure of prostaglandin H2 synthase-1:: Structural insights into an unusual peroxidase [J].

Gupta, K ;

Selinsky, BS ;

Kaub, CJ ;

Katz, AK ;

Loll, PJ .

JOURNAL OF MOLECULAR BIOLOGY, 2004, 335 (02) :503-518

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