ABSTRACT
The energetics and models of COX-2 complexed with nonsteroidal anti-inflammatory drugs (NSAIDs) having different degrees of selectivity for two isoforms of COX (COX-2 and COX-1) have been studied using computer modelling approach. The models are obtained for complexes of NS398 (NS), a selective COX-2 inhibitor; indoprofen (Ind), a non-selective inhibitor; di-tert-butylbenzofurans (DHDMBFs) with substituents at the 5th position: CONH(CH2)2OMe (BF1), CONH-c-Pr (BF2), 3-methylene-gamma-butyrolactonyl (BF3) and oxicams namely, meloxicam (Mel), piroxicam (Pir) and tenoxicam (Ten). These were optimized using molecular mechanics (MM) and molecular dynamics (MD) techniques. The binding energies and structures were compared with pharmacological parameters and available results with COX-1. In case of NS a larger difference in the binding energies between COX-2 and COX-1 was noticed as compared to that of Ind. It also had stronger interaction with His90 and Tyr355 which is considered important for COX-2 selectivity. There was a difference in the compactness at the channel entrance between COX-2 selective and non-selective ligands. Models with DHDMBFs and oxicams showed a similar correlation. The results were used to design a peptide inhibitor, Tyr-Arg-Cys-Ala-delta Phe-Cys (Pept) which could fit better in the COX-2 cavity. As per our MD simulation results this peptide inhibitor showed both higher activity and COX-2 selectivity.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Binding Sites , Cyclooxygenase 1 , Cyclooxygenase 2 , Inhibitory Concentration 50 , Isoenzymes/chemistry , Kinetics , Ligands , Models, Chemical , Models, Molecular , Monte Carlo Method , Prostaglandin-Endoperoxide Synthases/chemistry , Protein Binding , Protein Conformation , Software , Thermodynamics , X-Ray DiffractionABSTRACT
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.
Subject(s)
Arachidonate 5-Lipoxygenase/antagonists & inhibitors , Benzofurans/chemistry , Catalytic Domain , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/chemistry , Isoenzymes/chemistry , Lipoxygenase Inhibitors/chemistry , Models, Molecular , Molecular Conformation , Prostaglandin-Endoperoxide Synthases/chemistryABSTRACT
A casi un siglo de su aparición, la hipersensibilidad a la aspirina continúa siendo un enigma. Desde la primera publicación de una reacción anafiláctica inducida por aspirina realizada por Hirschberg en 1902, un gran acopio de información ha surgido en relación a la hipersensibilidad a la aspirina. Varias teorías se han propuesto, destacando la teoría de la inhibición de la ciclooxigenasa. En este artículo presentamos una revisión crítica de las teorías propuestas y damos un enfoque personal de la hipótesis de la alteración del metabolismo del ácido araquidónico en el asma inducida por aspirina