0000000001303977
AUTHOR
Edwin Winkler
Optimization of Triazine Nitriles as Rhodesain Inhibitors: Structure-Activity Relationships, Bioisosteric Imidazopyridine Nitriles, and X-ray Crystal Structure Analysis with Human Cathepsin L
The cysteine protease rhodesain of Trypanosoma brucei parasites causing African sleeping sickness has emerged as a target for the development of new drug candidates. Based on a triazine nitrile moiety as electrophilic headgroup, optimization studies on the substituents for the S1, S2, and S3 pockets of the enzyme were performed using structure-based design and resulted in inhibitors with inhibition constants in the single-digit nanomolar range. Comprehensive structure-activity relationships clarified the binding preferences of the individual pockets of the active site. The S1 pocket tolerates various substituents with a preference for flexible and basic side chains. Variation of the S2 subs…
CCDC 916055: Experimental Crystal Structure Determination
Related Article: Veronika Ehmke, Edwin Winkler, David W. Banner, Wolfgang Haap, W. Bernd Schweizer, Matthias Rottmann, Marcel Kaiser, Céline Freymond, Tanja Schirmeister, François Diederich|2013|ChemMedChem|8|967|doi:10.1002/cmdc.201300112
CCDC 916056: Experimental Crystal Structure Determination
Related Article: Veronika Ehmke, Edwin Winkler, David W. Banner, Wolfgang Haap, W. Bernd Schweizer, Matthias Rottmann, Marcel Kaiser, Céline Freymond, Tanja Schirmeister, François Diederich|2013|ChemMedChem|8|967|doi:10.1002/cmdc.201300112