The Identification, Characterization and Optimization of Small Molecule Probes of Cysteine Proteases: Experiences of the Penn Center for Molecular Discovery with Cathepsin B and Cathepsin L
Donna M. Huryn and Amos B. Smith III
Affiliation: Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104- 6323, USA.
During the pilot phase of the NIH Molecular Library Screening Network, the Penn Center for Molecular Discovery focused on a series of projects aimed at high throughput screening and the development of probes of a variety of protease targets. This review provides our medicinal chemistry experience with two such targets - cathepsin B and cathepsin L. We describe our approach for hit validation, characterization and triage that led to a critical understanding of the nature of hits from the cathepsin B project. In addition, we detail our experience at hit identification and optimization that led to the development of a novel thiocarbazate probe of cathepsin L.
Keywords: Cathepsin B, Cathepsin L, cysteine proteases, DTT, false positives, hit validation, hit triage, redox cycling, thiocarbazates
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