Comparative molecular modeling study of the three-dimensional structures of prostaglandin endoperoxide H2 synthase 1 and 2 (COX-1 and COX-2)

Marta Filizola, Juan J. Perez, Albert Palomer, David Mauleón

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36 Scopus citations

Abstract

To understand the structural features that dictate the selectivity of diverse nonsteroidal antiinflammatory drugs for the two isoforms of the human prostaglandin H2 synthase (PGHS), the three-dimensional (3D) structure of human COX-2 was assessed by means of sequence homology modeling. The ovine COX-1 structure, solved by X-ray diffraction methods and sharing a 61% sequence identity with human COX-2, was used as template. Both structures were energy minimized using the AMBER 4.0 force field with a dielectric constant of4r. (S)-Flurbiprofen, a nonselective COX inhibitor, and SC-558, a COX-2-selective ligand, were docked at the cyclooxygenase binding site in both isozymes, evidencing the role of different residues in the ligand-protein interaction. The 3D structures of the constructed four ligand-enzyme complexes were refined by energy minimization. Molecular dynamics simulations were also carried out, to understand more deeply the structural origins of selectivity. Distances calculated during the dynamics process between the different ligands and the interacting residues of the two PGHS isozymes provided evidence of the flexible nature of the cyclooxygenase active site, permitting the identification of different conserved and nonconserved residues as responsible for ligand selectivity.

Original languageEnglish
Pages (from-to)290-300
Number of pages11
JournalJournal of Molecular Graphics and Modelling
Volume15
Issue number5
DOIs
StatePublished - Oct 1997
Externally publishedYes

Keywords

  • AMBER force field
  • COX
  • Homology modeling
  • NSAIDs
  • PGHS

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