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Eur J Med Chem. 2017 Sep 29;138:661-668. doi: 10.1016/j.ejmech.2017.06.045. Epub 2017 Jun 24.

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

Author information

1
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Institute of Biomembranes and Bioenergetics, National Research Council, Via Amendola 165/A, 70125 Bari, Italy.
2
Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
3
Department of Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125 Catania, Italy.
4
Department of Pharmaceutical Sciences, College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USA.
5
Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
6
Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy. Electronic address: antonio.scilimati@uniba.it.

Abstract

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-yl)-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-(5-chlorofuran-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.

KEYWORDS:

Cyclooxygenase-1 inhibition; Diarylisoxazole; Mofezolac; Molecular modelling; P6; X-ray crystallography

PMID:
28710965
PMCID:
PMC5992922
DOI:
10.1016/j.ejmech.2017.06.045
[Indexed for MEDLINE]
Free PMC Article

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