Projects
Metabolic stability assessment
This project focuses on the development and application of biosynthetics by using P450 mutants and analytical technologies to generate and fully characterize novel compound libraries for drug discovery. Maarten Honing, research coordinator of the project: “In January 2008, the first project team meeting with all members was organized. We were able to reach all milestones in this first full year. Significant scientific progress was made. Two new P450 mutants were engineered. We validated the integrated workflow encompassing the biosynthesis of new steroidal metabolites. Other aspects addressed were the scaling up of this process, their on-line separation followed by MS/NMR structural characterization and the assessment of their binding affinities towards both ERalfa/beta receptors.” A complete paper describing the workflow is currently in release. In addition, an in-depth investigation of specific metabolite profiles, after site-directed mutagenesis of P450s, resulted in a scientific breakthrough in understanding the biotransformation mechanisms of action. For this purpose state-of-the-art NMR methodologies were developed.
Partners: MSD, Radboud University Nijmegen, VU University Amsterdam, and Xendo Drug Development BV
Full project title: Metabolic stability assessment as a new tool in the Hit-to-Lead selection process and the generation of new lead compound libraries