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 timeCrystallographyHigh-Throughput Crystallography: Reliable and Efficient Identification of Fragment Hits
Schiebel J, Krimmer S, Röwer K, Knörlein A, Wang X, Park A, Stieler M, Ehrmann F, Fu K, Radeva N, Krug M, Huschmann F, Glöckner S, Weiss M, Mueller U, Klebe G, Heine A. High-Throughput Crystallography: Reliable and Efficient Identification of Fragment Hits. Structure 2016, 24: 1398-1409. PMID: 27452405, DOI: 10.1016/j.str.2016.06.010.Peer-Reviewed Original ResearchConceptsFragment-like moleculesFragment-based methodsSubsequent drug designHigh-quality diffraction dataFragment hitsHit identificationLead structuresDiverse fragmentsDrug designThroughput CrystallographyDiffraction dataStructural informationProtein crystalsCrystallographyElectron densityRefinement pipelineLigandsDrug developmentCompoundsMoleculesRefinement cycleStructureSuccessful applicationLow affinityHitsImpact of Surface Water Layers on Protein–Ligand Binding: How Well Are Experimental Data Reproduced by Molecular Dynamics Simulations in a Thermolysin Test Case?
Betz M, Wulsdorf T, Krimmer S, Klebe G. Impact of Surface Water Layers on Protein–Ligand Binding: How Well Are Experimental Data Reproduced by Molecular Dynamics Simulations in a Thermolysin Test Case? Journal Of Chemical Information And Modeling 2016, 56: 223-233. PMID: 26691064, DOI: 10.1021/acs.jcim.5b00621.Peer-Reviewed Original ResearchConceptsObserved structure-activity relationshipsLocal water structureProtein-ligand bindingMolecular dynamics simulationsStructure-activity relationshipsHigh-resolution crystal structuresSolvation sitesWater structureSurface water networkWater rearrangementCrystal structureDesolvation effectsDifference electronMolecular dynamicsDynamics simulationsLigand portionWater networkDrug bindingContribution of waterWater layerComplexesSurface water layerWaterPhosphonamidatesStructure
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