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 stateMoleculesLigands
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 affinityHits