Recognition of cyclooxygenase-2 (COX-2) active site by NSAIDs: A computer modelling study

Abstract

The energetics and models of COX-2 complexed with nonsteroidal anti-innammatory 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 (<b>NS</b>), a selective COX-2 inhibitor; indoprofen (<b>Ind</b>), a nonselective inhibitor; di-<i>tert</i>-butylbenzofurans (DHDMBFs) with substituents at the 5th position: CONH(CH₂)₂ OMe (<b>BF1</b>),CONH-c-Pr (<b>BF2</b>), 3-methylene-γ- butyrolactonyl (<b>BF3</b>) and oxicams namely, meloxicam (<b>Mel</b>), piroxicam (<b>Pir</b>) and tenoxicam (<b>Ten</b>). 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 <b>COX-1</b>. In case of <b>NS</b> a larger difference in the binding energies between COX-2 and COX-1 was noticed as compared to that of <b>Ind</b>. It also had stronger interaction with Hi s90 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-ΔPhe- Cys (<b>Pept</b>) 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.