0000000001305764
AUTHOR
Jörg Benz
showing 10 related works from this author
Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide⋅⋅⋅Heteroarene π-Stacking Interactions and Chalcogen Bonding in the …
2016
We report an extensive "heteroarene scan" of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate π-stacking on the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket. This heteroarene⋅⋅⋅peptide bond stacking was supported by a co-crystal structure of an imidazopyridine ligand with hCatL. Inhibitory constants (Ki ) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroaromatic ligands feature enhanced binding by comparison with hydrocarbon analogues. Predicted energetic contributions from the ori…
Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.
2018
Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei (T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors (Ki < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys–SOH) during crystallization. The P-glycoprotein efflux ratio was mea…
Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors.
2017
Improving the binding affinity of a chemical series by systematically probing one of its exit vectors is a medicinal chemistry activity that can benefit from molecular modeling input. Herein, we compare the effectiveness of four approaches in prioritizing building blocks with better potency: selection by a medicinal chemist, manual modeling, docking followed by manual filtering, and free energy calculations (FEP). Our study focused on identifying novel substituents for the apolar S2 pocket of cathepsin L and was conducted entirely in a prospective manner with synthesis and activity determination of 36 novel compounds. We found that FEP selected compounds with improved affinity for 8 out of …
CCDC 1516759: Experimental Crystal Structure Determination
2017
Related Article: Bernd Kuhn, Michal Tichý, Lingle Wang, Shaughnessy Robinson, Rainer E. Martin, Andreas Kuglstatter, Jörg Benz, Maude Giroud, Tanja Schirmeister, Robert Abel, François Diederich, and Jérôme Hert|2017|J.Med.Chem.|60|2485|doi:10.1021/acs.jmedchem.6b01881
CCDC 1516760: Experimental Crystal Structure Determination
2017
Related Article: Bernd Kuhn, Michal Tichý, Lingle Wang, Shaughnessy Robinson, Rainer E. Martin, Andreas Kuglstatter, Jörg Benz, Maude Giroud, Tanja Schirmeister, Robert Abel, François Diederich, and Jérôme Hert|2017|J.Med.Chem.|60|2485|doi:10.1021/acs.jmedchem.6b01881
CCDC 1449741: Experimental Crystal Structure Determination
2017
Related Article: Maude Giroud, Jakov Ivkovic, Mara Martignoni, Marianne Fleuti, Nils Trapp, Wolfgang Haap, Andreas Kuglstatter, Jörg Benz, Bernd Kuhn, Tanja Schirmeister, François Diederich|2017|ChemMedChem|12|257|doi:10.1002/cmdc.201600563
CCDC 1516761: Experimental Crystal Structure Determination
2017
Related Article: Bernd Kuhn, Michal Tichý, Lingle Wang, Shaughnessy Robinson, Rainer E. Martin, Andreas Kuglstatter, Jörg Benz, Maude Giroud, Tanja Schirmeister, Robert Abel, François Diederich, and Jérôme Hert|2017|J.Med.Chem.|60|2485|doi:10.1021/acs.jmedchem.6b01881
CCDC 1516757: Experimental Crystal Structure Determination
2017
Related Article: Bernd Kuhn, Michal Tichý, Lingle Wang, Shaughnessy Robinson, Rainer E. Martin, Andreas Kuglstatter, Jörg Benz, Maude Giroud, Tanja Schirmeister, Robert Abel, François Diederich, and Jérôme Hert|2017|J.Med.Chem.|60|2485|doi:10.1021/acs.jmedchem.6b01881
CCDC 1516756: Experimental Crystal Structure Determination
2017
Related Article: Bernd Kuhn, Michal Tichý, Lingle Wang, Shaughnessy Robinson, Rainer E. Martin, Andreas Kuglstatter, Jörg Benz, Maude Giroud, Tanja Schirmeister, Robert Abel, François Diederich, and Jérôme Hert|2017|J.Med.Chem.|60|2485|doi:10.1021/acs.jmedchem.6b01881
CCDC 1516758: Experimental Crystal Structure Determination
2017
Related Article: Bernd Kuhn, Michal Tichý, Lingle Wang, Shaughnessy Robinson, Rainer E. Martin, Andreas Kuglstatter, Jörg Benz, Maude Giroud, Tanja Schirmeister, Robert Abel, François Diederich, and Jérôme Hert|2017|J.Med.Chem.|60|2485|doi:10.1021/acs.jmedchem.6b01881