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Conception par modélisation et criblage in silico d'inhibiteurs du récepteur c-Met

Yasmine Asses 1
1 ORPAILLEUR - Knowledge representation, reasonning
INRIA Lorraine, LORIA - Laboratoire Lorrain de Recherche en Informatique et ses Applications
Abstract : The challenge of this PhD work is the in silico identification of potentially interesting molecules concerning the inhibitory process of tyrosine kinase receptor c-Met. The faculty of this protein to interact in embryogenesis and tissue repair phenomena makes its inhibition crucial for treatments against tumor development in which c-Met is involved. For that purpose, the employed strategy involves the use of several in silico methods for rational drug design. As the basement of this work, we used the multiple crystal structures published in the ProteinData Base (PDB). A preliminary homology modeling work was needed to fill gaps in the crystal structures. To sample at best the c-Met kinase conformational space and to characterize its flexibility, a long Molecular Dynamics (MD) simulation campaign was carried out both on apo and holo forms of available crystal structures. To complete these simulations, part of this work consisted to use normal modes of vibration (NM) method. From these two approaches (DM and NM), we extracted a set of 10 conformers considered as the most representative of the kinase simulated conformational space and we suggested a mode of operation of this kinase. Using extracted conformations from the conformational sampling has enabled us to conduct an extensive campaign on several virtual screening libraries constituting a total of approximately 70,000 compounds. Analysis of the molecular docking results has led us to the selection of several theoretically interesting molecules with good potential affinity for c-Met kinase. These molecules were submitted to experimental tests performed by the biologist team associated to our work.
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Submitted on : Monday, December 19, 2011 - 6:00:16 PM
Last modification on : Monday, October 19, 2020 - 11:11:35 AM
Long-term archiving on: : Tuesday, March 20, 2012 - 2:50:10 AM


  • HAL Id : tel-01746221, version 2


Yasmine Asses. Conception par modélisation et criblage in silico d'inhibiteurs du récepteur c-Met. Chemo-informatique. Université Henri Poincaré - Nancy 1, 2011. Français. ⟨NNT : 2011NAN10081⟩. ⟨tel-01746221v2⟩



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