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Evaluation et application de méthodes de criblage in silico

Abstract : Since the introduction of virtual screening in the drug discovery process, the number ofvirtual screening methods has been increasing and available methods have to be evaluated.In this work, eight virtual screening methods were evaluated in the DUD database, showingadequate efficiency. This also revealed some shortcomings of the DUD database as thebinding site conformation used in the DUD was not relevant for all the actives.As computational power now permits to address this issue, classical docking runs have beenperformed on several X-ray structures, used to represent the binding site flexibility. This alsorevealed that evaluation metrics show some biases. New evaluation metrics have thus beenproposed, e.g. BEDROC and RIE. An alternative method was also proposed usingpredictiveness curves, based on compound activity probabilityFinally, a virtual screening procedure has been applied to TNFa. A small molecule inhibitor,showing in vitro and in vivo activity in mice, has been identified. This demonstrated the valueof virtual screening for the drug discovery process, although virtual screening methods needto be improved.
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Hélène Guillemain. Evaluation et application de méthodes de criblage in silico. Pharmacologie. Conservatoire national des arts et metiers - CNAM, 2012. Français. ⟨NNT : 2012CNAM0849⟩. ⟨tel-00814270⟩

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