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Automated docking and molecular dynamics simulations of nimesulide in the cyclooxygenase active site of human prostaglandin-endoperoxide synthase-2 (COX-2)

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Abstract

Molecular models of the complex between the selective COX-2 inhibitor nimesulide and the cyclooxygenase active site of human prostaglandin-endoperoxide synthase-2 have been built using a combination of homology modelling, conformational searching and automated docking techniques. The stability of the resulting complexes has been assessed by molecular dynamics simulations and interaction energy decomposition. It is found that nimesulide exploits the extra space made available by the replacement at position 523 of an isoleucine residue in COX-1 by a valine in COX-2 and establishes electrostatic interactions with both Arg-106 and Arg-499 (Arg-120 and Arg-513 in PGHS-1 numbering). Two alternate binding modes are proposed which are compatible with the pharmacological profile of this agent as a COX-2 selective inhibitor.

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Authors and Affiliations

  1. Departamento de Farmacología, Universidad de Alcalá, E-28871 Alcalá de Henares, Madrid, Spain

    Raquel García-Nieto, Carlos Pérez & Federico Gago

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  1. Raquel García-Nieto
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García-Nieto, R., Pérez, C. & Gago, F. Automated docking and molecular dynamics simulations of nimesulide in the cyclooxygenase active site of human prostaglandin-endoperoxide synthase-2 (COX-2). J Comput Aided Mol Des 14, 147–160 (2000). https://doi.org/10.1023/A:1008110924479

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