title: Exploring c-Met kinase flexibility by sampling and clustering its conformational space.
abstract: It is now widely recognized that the flexibility of both partners has to be considered in molecular docking studies. However, the question how to handle the best the huge computational complexity of exploring the protein binding site landscape is still a matter of debate. Here we investigate the flexibility of c-Met kinase as a test case for comparing several simulation methods. The c-Met kinase catalytic site is an interesting target for anticancer drug design. In particular, it harbors an unusual plasticity compared with other kinases ATP binding sites. Exploiting this feature may eventually lead to the discovery of new anticancer agents with exquisite specificity. We present in this article an extensive investigation of c-Met kinase conformational space using large-scale computational simulations in order to extend the knowledge already gathered from available X-ray structures. In the process, we compare the relevance of different strategies for modeling and injecting receptor flexibility information into early stage in silico structure-based drug discovery pipeline. The results presented here are currently being exploited in on-going virtual screening investigations on c-Met.
authors.affiliation: Nancy Université, LORIA/UMR 7503, Équipe-projet Orpailleur, Campus Scientifique, Vandœuvre-lès-Nancy Cedex, France.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Asses
authors.forename: Vishwesh
authors.initials: V
authors.lastname: Venkatraman
authors.forename: Vincent
authors.initials: V
authors.lastname: Leroux
authors.forename: David W
authors.initials: DW
authors.lastname: Ritchie
authors.forename: Bernard
authors.initials: B
authors.lastname: Maigret
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000465:Algorithms; D001665:Binding Sites; D016000:Cluster Analysis; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D010770:Phosphotransferases / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry*
chemical_list: D008024:Ligands; D000255:Adenosine Triphosphate; D010770:Phosphotransferases; D019859:Proto-Oncogene Proteins c-met