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In silico drug design et chimie médicinale : développement de nouvelles molécules coumariniques, sélectives de la cyclooxygénase-2

Abstract : Inflammation is a phenomenon affecting millions of people throughout the world. There is a broad range of inflammatory mediators implied in different biological functions including the cyclooxygenase-2. Although many selective inhibitors selective of COX-2 have been developed and marketed, they have displayed diverse side effects leading, in some cases, to their with drawal from the market. Nowadays, in silico methods are more and more used in the drug discovery process. In this project, we have used pharmacophoric models and docking methods to guide and prioritize the synthesis of molecules, presenting different and original structures, with enhanced affinity for the biological target. Thus, predictions realized with the TOMOCOMD-CARDD software together with biological tests enable to identify the cyclocoumarol as a potential anti-inflammatory molecule. As part of these works, the synthesis of and the study of cyclocoumarol analogues as selective inhibitors of COX-2 have been realized. Pharmacomodulation of cyclocoumarol and development of synthesis strategies led to a serie of cyclocoumarol analogues. Several bioinformatics tools have been used: selective COX-2 pharmacophores were elucidated using LigandScout and docking studies (Surflex) were conducted to understand the binding mode of different compounds. Finally, SeeSAR enabled to predict the affinity of the molecules the most susceptible to inhibit selectively COX-2. Biological tests confirmed their inhibitory activity against COX-2 and showed no significant inhibition for COX-1. Among the synthesized molecules, the 4-OMe cyclocoumarol has demonstrated an activity and a selectivity very interesting, similar to NS-398, a known selective COX-2 inhibitor.Based on the biological results obtained, a pharmacomodulation study of cyclocoumarol derivatives has been realized using in silico tools in order to predict the affinity of new compounds and to discover new selective inhibitors of COX-2.Keywords : cyclocoumarol, benzalacetones, warfarines, pharmacophores, docking, virtual screening, COX-2, repositioning
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Submitted on : Monday, December 11, 2017 - 11:16:56 PM
Last modification on : Friday, September 13, 2019 - 3:54:01 PM


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  • HAL Id : tel-01661380, version 1



Anita-Marie Rayar. In silico drug design et chimie médicinale : développement de nouvelles molécules coumariniques, sélectives de la cyclooxygénase-2. Médecine humaine et pathologie. Conservatoire national des arts et metiers - CNAM, 2017. Français. ⟨NNT : 2017CNAM1085⟩. ⟨tel-01661380⟩



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