2017
How Nothing Boosts Affinity: Hydrophobic Ligand Binding to the Virtually Vacated S1′ Pocket of Thermolysin
Krimmer S, Cramer J, Schiebel J, Heine A, Klebe G. How Nothing Boosts Affinity: Hydrophobic Ligand Binding to the Virtually Vacated S1′ Pocket of Thermolysin. Journal Of The American Chemical Society 2017, 139: 10419-10431. PMID: 28696673, DOI: 10.1021/jacs.7b05028.Peer-Reviewed Original ResearchConceptsWater moleculesPresent water moleculesWeak-binding ligandsAliphatic side chainsSpecificity pocketIsothermal titration calorimetrySolvent moleculesHigh-resolution crystallographyActive siteHydrophobic ligand bindingCrystalline stateElectron density mapsSide chainsTitration calorimetryS1 pocketNoble gas atomsSubstituentsThermodynamic signaturesFree energyHydration stateMoleculesLigandsPaying the Price of Desolvation in Solvent-Exposed Protein Pockets: Impact of Distal Solubilizing Groups on Affinity and Binding Thermodynamics in a Series of Thermolysin Inhibitors
Cramer J, Krimmer S, Heine A, Klebe G. Paying the Price of Desolvation in Solvent-Exposed Protein Pockets: Impact of Distal Solubilizing Groups on Affinity and Binding Thermodynamics in a Series of Thermolysin Inhibitors. Journal Of Medicinal Chemistry 2017, 60: 5791-5799. PMID: 28590130, DOI: 10.1021/acs.jmedchem.7b00490.Peer-Reviewed Original ResearchConceptsPolar groupsThermolysin inhibitorsProtein pocketFirst hydration shellProtein-ligand complexesProtein-solvent interfaceProspective binding sitesWater moleculesHydration shellSolvent effectsAmmonium groupsPartial desolvationSolvent-exposed positionsBinding thermodynamicsWater reorganizationThermodynamic fingerprintLead optimizationInhibitor scaffoldsHydrophobic analoguesDesolvationPharmacokinetic propertiesOpen pocket
2016
Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein-Bound Ligands
Krimmer S, Cramer J, Betz M, Fridh V, Karlsson R, Heine A, Klebe G. Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein-Bound Ligands. Journal Of Medicinal Chemistry 2016, 59: 10530-10548. PMID: 27933956, DOI: 10.1021/acs.jmedchem.6b00998.Peer-Reviewed Original ResearchConceptsDifferent hydrophobic substituentsKinetic binding profilesProtein-bound ligandsParent ligandSurface plasmon resonanceWater moleculesProtein-bound inhibitorThermolysin inhibitorsHigh-resolution crystallographyCongeneric seriesRational designWater networkMD simulationsHydrophobic substituentsPlasmon resonanceSubstituentsAffinity enhancementLigandsWater polygonsWater layerSurface water networkSurface water layerBinding signatureResidence timeCrystallographyActive Site Mapping of an Aspartic Protease by Multiple Fragment Crystal Structures: Versatile Warheads To Address a Catalytic Dyad
Radeva N, Schiebel J, Wang X, Krimmer S, Fu K, Stieler M, Ehrmann F, Metz A, Rickmeyer T, Betz M, Winquist J, Park A, Huschmann F, Weiss M, Mueller U, Heine A, Klebe G. Active Site Mapping of an Aspartic Protease by Multiple Fragment Crystal Structures: Versatile Warheads To Address a Catalytic Dyad. Journal Of Medicinal Chemistry 2016, 59: 9743-9759. PMID: 27726357, DOI: 10.1021/acs.jmedchem.6b01195.Peer-Reviewed Original ResearchConceptsFunctional groupsAspartic protease endothiapepsinCatalytic dyadCarboxylic acid fragmentOxygen functional groupsNovel functional groupsActive site mappingSteric demandWater moleculesFragment-growing strategyCrystal structureSide chainsFragment libraryHigh-quality crystalsS1 pocketScreening cascadeAcid fragmentCrystallographySpecificity pocketRelated fragmentsWarhead
2014
Methyl, Ethyl, Propyl, Butyl: Futile But Not for Water, as the Correlation of Structure and Thermodynamic Signature Shows in a Congeneric Series of Thermolysin Inhibitors
Krimmer S, Betz M, Heine A, Klebe G. Methyl, Ethyl, Propyl, Butyl: Futile But Not for Water, as the Correlation of Structure and Thermodynamic Signature Shows in a Congeneric Series of Thermolysin Inhibitors. ChemMedChem 2014, 9: 833-846. PMID: 24623396, DOI: 10.1002/cmdc.201400013.Peer-Reviewed Original ResearchConceptsWater moleculesFirst solvation layerThermodynamic binding profilesProtein-ligand binding processHigh-resolution crystal structuresIsothermal titration calorimetrySolvation patternsCorrelation of structureSolvation layerEntropy-driven bindingThermolysin inhibitorsCongeneric seriesSingle methyl groupCrystal structureWater arrangementSolvent-exposed surfaceTitration calorimetryBinding processMethyl groupS2 pocketSubstituentsComplex formationBinding propertiesLigand binding propertiesBiological systems