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

V Kothekar, S Sahi, M Srinivasan, A Mohan, J Mishra

Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India. kothekar@hotmail.com

Indian journal of biochemistry & biophysics 2001 Feb-Apr

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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.

Citation

V Kothekar, S Sahi, M Srinivasan, A Mohan, J Mishra. Recognition of cyclooxygenase-2 (COX-2) active site by NSAIDs: a computer modelling study. Indian journal of biochemistry & biophysics. 2001 Feb-Apr;38(1-2):56-63