Enzyme selectivity of new cyclooxygenase-2/5 lipoxygenase inhibitors using molecular modeling approach.

We have studied the conformational flexibility of three 5-keto-substituted 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) which show dual cyclooxygenase (COX) and 5-lipoxygenase (LOX) inhibition and are potential candidates as antiinflammatory agents and analgesics. The conformations were studied by systematic search, molecular mechanics (MM) and simulated annealing molecular dynamics (SAMD) techniques. We also studied several structure based parameters and distribution of molecular electrostatic potential (MEP) around these molecules. All the three compounds were docked in the active cavity of cyclooxygenase-2 (COX-2) using graphical and energy grid search techniques. The complex geometries were optimized by MM. The results on conformational flexibility, inter-atomic distances and angles, MEP distribution and points of contacts with peptide side chains in active cavity have been used to understand the mechanistic cause of differential action of these molecules.