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

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Title Recognition of cyclooxygenase-2 (COX-2) active site by NSAIDs: A computer modelling study
 
Creator Kothekar, V
Sahi, S
Srinivasan, M
Mohan, A
Mishra, J
 
Description 56-63
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 (NS), a selective COX-2 inhibitor; indoprofen (Ind), a nonselective inhibitor; di-tert-butylbenzofurans
(DHDMBFs) with substituents at the 5th position: CONH(CH2)2
OMe (BF1),CONH-c-Pr
(BF2), 3-methylene-γ- 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 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 (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.
 
Date 2013-07-16T06:03:48Z
2013-07-16T06:03:48Z
2001-04
 
Type Article
 
Identifier 0975-0959 (Online); 0301-1208 (Print)
http://hdl.handle.net/123456789/19799
 
Language en_US
 
Rights CC Attribution-Noncommercial-No Derivative Works 2.5 India
 
Publisher NISCAIR-CSIR, India
 
Source IJBB Vol.38(1-2) [February-April 2001]