2021
Structural basis for ligand reception by anaplastic lymphoma kinase
Li T, Stayrook SE, Tsutsui Y, Zhang J, Wang Y, Li H, Proffitt A, Krimmer SG, Ahmed M, Belliveau O, Walker IX, Mudumbi KC, Suzuki Y, Lax I, Alvarado D, Lemmon MA, Schlessinger J, Klein DE. Structural basis for ligand reception by anaplastic lymphoma kinase. Nature 2021, 600: 148-152. PMID: 34819665, PMCID: PMC8639777, DOI: 10.1038/s41586-021-04141-7.Peer-Reviewed Original Research
2018
Optimization of Pyrazoles as Phenol Surrogates to Yield Potent Inhibitors of Macrophage Migration Inhibitory Factor
Trivedi‐Parmar V, Robertson MJ, Cisneros J, Krimmer SG, Jorgensen WL. Optimization of Pyrazoles as Phenol Surrogates to Yield Potent Inhibitors of Macrophage Migration Inhibitory Factor. ChemMedChem 2018, 13: 1092-1097. PMID: 29575754, PMCID: PMC5990473, DOI: 10.1002/cmdc.201800158.Peer-Reviewed Original Research
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 ResearchMeSH KeywordsBinding SitesCalorimetryCrystallography, X-RayHumansHydrophobic and Hydrophilic InteractionsLigandsModels, MolecularThermodynamicsThermolysinConceptsWater 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
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 releaseActive 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 ResearchMeSH KeywordsAspartic Acid ProteasesBiocatalysisCalorimetryCarboxylic AcidsCatalytic DomainCrystallography, X-RayHydrazinesModels, MolecularPyrazolesConceptsFunctional 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 fragmentsWarheadExperimental Active-Site Mapping by Fragments: Hot Spots Remote from the Catalytic Center of Endothiapepsin
Radeva N, Krimmer S, Stieler M, Fu K, Wang X, Ehrmann F, Metz A, Huschmann F, Weiss M, Mueller U, Schiebel J, Heine A, Klebe G. Experimental Active-Site Mapping by Fragments: Hot Spots Remote from the Catalytic Center of Endothiapepsin. Journal Of Medicinal Chemistry 2016, 59: 7561-7575. PMID: 27463859, DOI: 10.1021/acs.jmedchem.6b00645.Peer-Reviewed Original ResearchHigh-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 ResearchMeSH KeywordsCrystallography, X-RayDatasets as TopicDrug DesignHigh-Throughput Screening AssaysHumansSmall Molecule LibrariesWaterX-Ray DiffractionConceptsFragment-like moleculesFragment-based methodsSubsequent drug designHigh-quality diffraction dataFragment hitsHit identificationLead structuresDiverse fragmentsDrug designThroughput CrystallographyDiffraction dataStructural informationProtein crystalsCrystallographyElectron densityRefinement pipelineLigandsDrug developmentCompoundsMoleculesRefinement cycleStructureSuccessful applicationLow affinityHitsSix Biophysical Screening Methods Miss a Large Proportion of Crystallographically Discovered Fragment Hits: A Case Study
Schiebel J, Radeva N, Krimmer S, Wang X, Stieler M, Ehrmann F, Fu K, Metz A, Huschmann F, Weiss M, Mueller U, Heine A, Klebe G. Six Biophysical Screening Methods Miss a Large Proportion of Crystallographically Discovered Fragment Hits: A Case Study. ACS Chemical Biology 2016, 11: 1693-1701. PMID: 27028906, DOI: 10.1021/acschembio.5b01034.Peer-Reviewed Original Research