2017
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
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
Elucidating the Origin of Long Residence Time Binding for Inhibitors of the Metalloprotease Thermolysin
Cramer J, Krimmer S, Fridh V, Wulsdorf T, Karlsson R, Heine A, Klebe G. Elucidating the Origin of Long Residence Time Binding for Inhibitors of the Metalloprotease Thermolysin. ACS Chemical Biology 2016, 12: 225-233. PMID: 27959500, DOI: 10.1021/acschembio.6b00979.Peer-Reviewed Original ResearchConceptsCharge-assisted hydrogen bondsMetalloprotease thermolysinSurface plasmon resonance spectroscopyDrug discoveryHigh-resolution crystal structuresPlasmon resonance spectroscopyKinetic dataProtein-ligand interactionsStructure-kinetic relationshipsRational drug discoveryHigh conservationHydrogen bondsDissociation rate constantsStrength of interactionThermolysin inhibitorsMetalloprotease familyCrystal structureMolecular mechanismsSide chainsStrand motifResonance spectroscopyStructural motifsRate constantsRate-limiting stepLigand releaseRational 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 timeCrystallography
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