6-Alkyl, alkoxy, or alkylthio-substituted 3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones: A novel class of diarylheterocyclic selective cyclooxygenase-2 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 13, 2003, Pages 2205-2209

  Rao, P N Praveen ^a   Amini, Mohsen ^a   Li, Huiying ^a   Habeeb, Amgad G ^a   Knaus, Edward E ^a  

^a UNIVERSITY OF ALBERTA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLOOXYGENASE 2 INHIBITOR; PYRAN DERIVATIVE;

ARTICLE; DRUG DESIGN; DRUG SCREENING; DRUG SYNTHESIS; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

EID: 0037533960     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(03)00391-3     Document Type: Article

References (20)

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19. Docking studies were performed using Insight II software Version 2000.1 (Accelrys Inc.) running on a Silicon Graphics Octane 2 R14000A workstation. The coordinates of the X-ray crystal structure of the selective COX-2 inhibitor SC-558 bound to the murine COX-2 enzyme was obtained from the RCSB Protein Data Bank (1cx2) and hydrogens were added. The ligand molecules were constructed using the Builder module and were energy minimized for 1000 iterations reaching a convergence of 0.01 kcal/mol Å. The energy minimized ligands were superimposed on SC-558 in the PDB file 1cx2 after which SC-558 was deleted. The resulting structure (ligand-enzyme assembly) was minimized using the Discover module for 5000 iterations or until an RMSD of 0.05 Å was reached using consistent valence force field (CVFF). Further optimization of the ligand-enzyme complex was obtained using the Affinity command in the Docking module of Insight II by defining subsets of the enzyme such that residues within 10 Å of the ligand were allowed to relax, while the rest of the enzyme residues were fixed. The optimal binding orientation was achieved by utilizing 300 steps of steepest descent followed by the conjugate gradient method. The CVFF was employed for all docking purposes. These docked structures were very similar to the minimized structures obtained initially. The quality of the docked structures were evaluated by measuring the intermolecular energy of the ligand-enzyme assembly.
20. 2: C 62.16, H 4.69. Found: C 62.04, H 4.85.