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

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

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

Indian J Biochem Biophys. 2001 Feb-Apr;38(1-2):56-63.

PubMed ID

11563332 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tenoxicam	Prostaglandin G/H synthase 1	Protein	Humans	Unknown	Inhibitor	Details
Tenoxicam	Prostaglandin G/H synthase 2	Protein	Humans	Yes	Inhibitor	Details