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 ResearchMeSH KeywordsBinding SitesDose-Response Relationship, DrugKineticsLigandsMolecular Dynamics SimulationMolecular StructureProteinsStructure-Activity RelationshipSurface PropertiesThermodynamicsWaterConceptsDifferent 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 timeCrystallographyImpact 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 ResearchMeSH KeywordsDrug DesignLigandsMolecular Dynamics SimulationProtein BindingProtein ConformationReproducibility of ResultsStructure-Activity RelationshipThermodynamicsThermolysinWaterConceptsObserved 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