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Développement d'une méthode pour la détection de cibles secondaires de ligands

Abstract : Detection of putative off-targets for a ligand requires to search for some similarbinding sites onto other proteins surface. In order to achieve this goal, we developeda tool named PatchSearch. This program compares a query patch, whichcontains the binding site, with the surface a potentially targeted protein. Patch-Search’s algorithm is based on an original method searching for some quasi-cliquesin a graph product, which identifies some atoms both in the patch and in the surfacewith conserved physicochemical properties and in similar configurations. Weshow that PatchSearch efficiently finds known patches on protein surfaces. Moreover,application of PatchSearch on flexible proteins shows that, unlike the classiccliques approach, quasi-cliques method allows to find both rigid and flexible partsof the patches. PatchSearch gets similar results compared to the other binding sitecomparison tools. We also applied PatchSearch to find patches binding polypharmacologicaldrugs involved in cancer treatment, in order to identify them on knownoff targets. Our experiments suggest to employ PatchSearch in off-targets detectionprocess.
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Inès Rasolohery. Développement d'une méthode pour la détection de cibles secondaires de ligands. Bio-informatique [q-bio.QM]. Université Sorbonne Paris Cité, 2016. Français. ⟨NNT : 2016USPCC172⟩. ⟨tel-01692486⟩

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