Thursday, 14th March, 2013, 12.00-13.00

Using docking and molecular dynamics to design drugs

We have discovered by high-throughput fragment-based docking several novel chemotypes of potent (single-digit nanomolar) and selective tyrosine kinase inhibitors [1-4].  Explicit solvent molecular dynamics has played an important role for the in silico validation of binding modes and  the selection of compounds for testing in vitro.  Definitive validation of the binding mode has been obtained by X-ray crystallography in our group [1,2].  The most advanced of our tyrosine kinase inhibitors are active on a subset of the NCI 60 cancer cell lines.  Furthermore, some of our  inhibitors have shown good pharmacokinetic properties in mice (including oral bioavailability) and are being currently selected for testing in tumor xenograft models.

[1] K. Lafleur et al. Structure-based Optimization of Inhibitors of the Tyrosine Kinase EphB4. Part 2: Cellular Potency Improvement and Binding Mode Validation by X-ray Crystallography. J. Med. Chem. 56, 84, 2013.

[2] H. Zhao, J. Dong, K. Lafleur, C. Nevado, and A. Caflisch.
Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics. ACS Med. Chem. Lett. 3, 834, 2012.

[3] H. Zhao, D. Huang, and A. Caflisch. Discovery of tyrosine kinase inhibitors by docking into an inactive kinase conformation generated by molecular dynamics. ChemMedChem 7, 1983, 2012.

[4] K. Lafleur et al. Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4). J. Med. Chem. 52, 6433, 2009.

Speaker: Amedeo Caflisch, Computational Structural Biology, University of Zurich, Switzerland.

Room Seminar room 473.10