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Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
Published on: July 25, 2013
Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators
Willem-Jan Keune1, Frances Potjewyd2, Tatjana Heidebrecht1
1Division of Biochemistry, The Netherlands Cancer Institute , Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
Abstract:
Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA) and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.
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