0000000001311558

AUTHOR

Nils Trapp

showing 3 related works from this author

Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings…

2016

The π-stacking of fluorinated benzene rings on protein backbone amide groups was investigated, using a dual approach comprising enzyme-ligand binding studies complemented by high-level quantum chemical calculations. In the experimental study, the phenyl substituent of triazine nitrile inhibitors of human cathepsin L (hCatL), which stacks onto the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket, was systematically fluorinated, and differences in inhibitory potency were measured in a fluorimetric assay. Binding affinity is influenced by lipophilicity (clog P), the dipole and quadrupole moments of the fluorinated rings, but also by additional interactions of the introduced fluo…

HalogenationNitrileStereochemistryCathepsin LStackingSubstituentchemistry.chemical_elementPeptideCysteine Proteinase InhibitorsMolecular Dynamics SimulationLigands010402 general chemistry01 natural sciencesBiochemistrychemistry.chemical_compoundAmideDrug DiscoveryHumansPeptide bondFluorometryGeneral Pharmacology Toxicology and PharmaceuticsTriazinePharmacologychemistry.chemical_classificationBinding SitesTriazines010405 organic chemistryOrganic ChemistryFluorineAmidesProtein Structure Tertiary0104 chemical sciencesKineticschemistryFluorineQuantum TheoryMolecular MedicineHydrophobic and Hydrophilic InteractionsChemMedChem
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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…

ImidazopyridineNitrileStereochemistryCathepsin LPeptideMolecular Dynamics Simulation010402 general chemistryCrystallography X-RayLigands01 natural sciencesBiochemistrychemistry.chemical_compoundAmideDrug DiscoveryHydrolaseNitrilesPeptide bondHumansGeneral Pharmacology Toxicology and PharmaceuticsTriazinePharmacologychemistry.chemical_classificationBinding Sites010405 organic chemistryChemistryLigandTriazinesOrganic ChemistryAmides0104 chemical sciencesProtein Structure TertiaryMolecular MedicineChalcogensQuantum TheoryProtein BindingChemMedChem
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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

Space GroupCrystallographyCrystal SystemCrystal StructureCell Parameters4-(benzyl(cyclopentyl)amino)-6-(morpholin-4-yl)-135-triazine-2-carbonitrileExperimental 3D Coordinates
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