2023
Positive allosteric modulators of the α7 nicotinic acetylcholine receptor: SAR investigation around PNU-120596
Acker B, Badescu V, Berkenpas M, Groppi V, Hajós M, Higdon N, Hurst R, Jacobsen E, Margolis B, McWhorter W, Myers J, Piotrowski D, Rogers B, Sarapa D, Vetman T, Walker D, Wall T, Wilhite D, Wishka D, Xu W, Yates K. Positive allosteric modulators of the α7 nicotinic acetylcholine receptor: SAR investigation around PNU-120596. Bioorganic & Medicinal Chemistry Letters 2023, 93: 129433. PMID: 37557923, DOI: 10.1016/j.bmcl.2023.129433.Peer-Reviewed Original ResearchConceptsΑ7 nicotinic acetylcholine receptorNicotinic acetylcholine receptorsPositive allosteric modulatorsAcetylcholine receptorsPNU-120596Powerful positive allosteric modulatorAllosteric modulatorsRat hippocampal neuronsPresence of acetylcholineDose-dependent mannerLigand-gated ion channelsCerebral cortexRat modelHippocampal neuronsSynaptic transmissionSensory gatingReceptorsEnhanced potencyIon channelsUnique biologyInitial structure-activity relationshipsSAR investigationCompound 16Structure-activity relationshipsThalamus
2022
Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors
Gannam Z, Jamali H, Kweon OS, Herrington J, Shillingford SR, Papini C, Gentzel E, Lolis E, Bennett AM, Ellman JA, Anderson KS. Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors. European Journal Of Medicinal Chemistry 2022, 243: 114712. PMID: 36116232, PMCID: PMC9830533, DOI: 10.1016/j.ejmech.2022.114712.Peer-Reviewed Original ResearchMeSH KeywordsStructure-Activity RelationshipConceptsStress-responsive MAPKsEnzyme-inhibitor complexDystrophic muscle diseasePhosphatase 5Muscle diseaseAllosteric inhibitorsNumber of diseasesNovel classProtein kinase phosphatase 5Structure-activity relationshipsPotential therapeutic targetMKP5X-ray crystal structureTherapeutic targetPotential therapeuticsInhibitorsLead compoundsInhibitionProper positioningMAPKCrystal structureMitogenTyr435Derivative compoundsInteraction
2021
Probing Microbiome Genotoxicity: A Stable Colibactin Provides Insight into Structure–Activity Relationships and Facilitates Mechanism of Action Studies
Wernke KM, Tirla A, Xue M, Surovtseva YV, Menges FS, Herzon SB. Probing Microbiome Genotoxicity: A Stable Colibactin Provides Insight into Structure–Activity Relationships and Facilitates Mechanism of Action Studies. Journal Of The American Chemical Society 2021, 143: 15824-15833. PMID: 34524796, DOI: 10.1021/jacs.1c07559.Peer-Reviewed Original ResearchConceptsFanconi anemia DNA repair pathwayBiosynthetic gene clusterDNA repair pathwaysGene clusterRepair pathwaysDNA bindingBacterial phenotypesInduces DNAGenotoxic effectsHuman microbiomeColibactinBiosynthetic precursorNatural product structuresBiological studiesPathwayStructure-activity relationshipsAction studiesGenotoxic metabolitesOrganismsOncogenesisDNATumorigenesisMicrobiomeFacilitate mechanismsPhenotypeEffective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection
Chiu JE, Renard I, Pal AC, Singh P, Vydyam P, Thekkiniath J, Kumar M, Gihaz S, Pou S, Winter RW, Dodean R, Frueh L, Nilsen AC, Riscoe MK, Doggett JS, Mamoun C. Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection. Antimicrobial Agents And Chemotherapy 2021, 65: 10.1128/aac.00662-21. PMID: 34152821, PMCID: PMC8370247, DOI: 10.1128/aac.00662-21.Peer-Reviewed Original ResearchConceptsEndochin-like quinolonesLethal infectionBlood-borne diseasesBlood-borne pathogensEffective therapyRelated apicomplexan parasitesExperimental therapiesLow doseMouse modelInfectious agentsHuman infectionsInfectionClinical candidatesStrong efficacyB. microtiExcellent safetyMode of actionTherapyErythrocytic developmentAtovaquoneEfficacyApicomplexan parasitesSafetyStructure-activity relationshipsParasitemiaStructure-guided design of a perampanel-derived pharmacophore targeting the SARS-CoV-2 main protease
Deshmukh MG, Ippolito JA, Zhang CH, Stone EA, Reilly RA, Miller SJ, Jorgensen WL, Anderson KS. Structure-guided design of a perampanel-derived pharmacophore targeting the SARS-CoV-2 main protease. Structure 2021, 29: 823-833.e5. PMID: 34161756, PMCID: PMC8218531, DOI: 10.1016/j.str.2021.06.002.Peer-Reviewed Original ResearchConceptsMain proteaseSARS-CoV-2 main proteaseActive site flexibilityDetailed structural insightsStructure-activity relationshipsInhibitor design effortsLow micromolar rangeActive site cysteineChemical scaffoldsLow nanomolar rangeCovalent adductsStructure-guided designCrystal structureStructural insightsPharmacophoreAdductsAttractive targetScaffoldsCysteineAnaloguesMechanism of actionSupRangeStructure
2020
Structural Optimization of Polymeric Carriers to Enhance the Immunostimulatory Activity of Molecularly Defined RIG‑I Agonists
Jacobson ME, Becker KW, Palmer CR, Pastora LE, Fletcher RB, Collins KA, Fedorova O, Duvall CL, Pyle AM, Wilson JT. Structural Optimization of Polymeric Carriers to Enhance the Immunostimulatory Activity of Molecularly Defined RIG‑I Agonists. ACS Central Science 2020, 6: 2008-2022. PMID: 33274278, PMCID: PMC7706089, DOI: 10.1021/acscentsci.0c00568.Peer-Reviewed Original ResearchPolymeric carriersNew structure-activity relationshipsPH-responsive propertiesAlkyl methacrylate monomersIntracellular deliveryAlkyl chain lengthInefficient intracellular deliverySeries of PEGEndosomal escapeNovel polymeric carriersNucleic acid therapeuticsLead carrierStructure-activity relationshipsPolymer structureMethacrylate monomerPolymer compositionChain lengthPolymeric deliveryMonomer compositionPolymersMajor clearance organVariable compositionDiameter particlesMolecularlyCarriersIdentification of small molecules by screening a mixture-based scaffold compound library for treatment of alpha-1 antitrypsin deficiency
Zhang X, Santos R, Debevec G, Li D, Schutte R, Pham K, Liu C, Ostrov DA, Giulianotti M. Identification of small molecules by screening a mixture-based scaffold compound library for treatment of alpha-1 antitrypsin deficiency. Biochemical And Biophysical Research Communications 2020, 527: 317-323. PMID: 32446387, DOI: 10.1016/j.bbrc.2020.04.037.Peer-Reviewed Original ResearchConceptsSmall moleculesCompound librariesStructural diversityActive compoundsPreliminary structure-activity relationshipScaffold libraryIndividual active compoundsStructure-activity relationshipsMixture librariesTitration experimentsCrystal structureMolecular dockingPolymerization sitePromising scaffoldCompoundsMixture formatMoleculesPosition R1Mixture samplesScaffoldsPotential binding sitesBinding sitesDocking
2019
Monofunctional platinum(II) compounds and nucleolar stress: is phenanthriplatin unique?
McDevitt CE, Yglesias MV, Mroz AM, Sutton EC, Yang MC, Hendon CH, DeRose VJ. Monofunctional platinum(II) compounds and nucleolar stress: is phenanthriplatin unique? JBIC Journal Of Biological Inorganic Chemistry 2019, 24: 899-908. PMID: 31494760, PMCID: PMC7660985, DOI: 10.1007/s00775-019-01707-9.Peer-Reviewed Original ResearchConceptsStructure-activity relationships
2018
Editing N-Glycan Site Occupancy with Small-Molecule Oligosaccharyltransferase Inhibitors
Rinis N, Golden JE, Marceau CD, Carette JE, Van Zandt MC, Gilmore R, Contessa JN. Editing N-Glycan Site Occupancy with Small-Molecule Oligosaccharyltransferase Inhibitors. Cell Chemical Biology 2018, 25: 1231-1241.e4. PMID: 30078634, PMCID: PMC6337728, DOI: 10.1016/j.chembiol.2018.07.005.Peer-Reviewed Original ResearchConceptsNGI-1Cellular unfolded protein responseMultisubunit enzyme complexN-glycan site occupancyUnfolded protein responseSubset of glycoproteinsSubunit-specific inhibitorsSecretory pathwayCatalytic subunitProtein responseEnzyme complexTarget proteinsOligosaccharyltransferasePharmacologic inhibitionGlycosylationProteinCell modelBiological effectsInhibitorsStructure-activity relationshipsSTT3BSTT3APharmacological approachesSubunitsSite occupancyEfficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships
Burslem GM, Ottis P, Jaime‐Figueroa S, Morgan A, Cromm PM, Toure M, Crews C. Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships. ChemMedChem 2018, 13: 1508-1512. PMID: 29870139, PMCID: PMC6291207, DOI: 10.1002/cmdc.201800271.Peer-Reviewed Original ResearchConceptsOne-pot synthesisIMiD analoguesStructure-activity relationshipsNarrow structure-activity relationshipMultiple purification stepsEfficient synthesisStepwise routePurification stepsSynthesisAnti-proliferative activityRapid accessProtein cereblonAiolos degradationFunctionalizationAnaloguesCompoundsMoleculesDegradationHereinPurificationRouteAffinityCereblon
2015
A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand
Teodoro R, Scheunemann M, Deuther-Conrad W, Wenzel B, Fasoli FM, Gotti C, Kranz M, Donat CK, Patt M, Hillmer A, Zheng MQ, Peters D, Steinbach J, Sabri O, Huang Y, Brust P. A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand. Molecules 2015, 20: 18387-18421. PMID: 26473809, PMCID: PMC6332508, DOI: 10.3390/molecules201018387.Peer-Reviewed Original ResearchMeSH Keywordsalpha7 Nicotinic Acetylcholine ReceptorAnimalsAza CompoundsBrainBrain MappingFluorine RadioisotopesHaplorhiniHumansHydrogen BondingKineticsLigandsOxidesPiperazinesPositron-Emission TomographyProtein BindingRadiopharmaceuticalsRatsReceptors, Serotonin, 5-HT3Structure-Activity RelationshipSwineThiophenesTissue DistributionConceptsStructure-activity relationshipsCationic centerPositron emission tomographyHydrogen bond acceptor functionalitiesNicotinic acetylcholine receptorsAcceptor functionalitiesAcetylcholine receptorsNew ligandsDibenzothiophene dioxideΑ7 nicotinic acetylcholine receptorCompound 7Promising PET tracerNew basic structureRadioligand displacement studiesTwo-tissue compartment modelLigandsEmission tomographyPET radioligandKinetic analysisFurther evaluationDynamic positron emission tomographyPET tracersInitial evaluationVivo evaluationBrainStructure–Activity Relationship for the Oxadiazole Class of Antibiotics
Spink E, Ding D, Peng Z, Boudreau M, Leemans E, Lastochkin E, Song W, Lichtenwalter K, O’Daniel P, Testero S, Pi H, Schroeder V, Wolter W, Antunes N, Suckow M, Vakulenko S, Chang M, Mobashery S. Structure–Activity Relationship for the Oxadiazole Class of Antibiotics. Journal Of Medicinal Chemistry 2015, 58: 1380-1389. PMID: 25590813, PMCID: PMC6863074, DOI: 10.1021/jm501661f.Peer-Reviewed Original ResearchConceptsMethicillin-resistant S. aureusStructure-activity relationshipsOxadiazole classClasses of antibioticsLinezolid-resistant S. aureusS. aureusMRSA infectionLead structuresCrystal structureMouse modelIndol-5Lower clearanceExhibit activityAntibioticsSilico dockingBacterium Staphylococcus aureusStaphylococcus aureusInfectionGram-positive bacterium Staphylococcus aureusCell wall biosynthesisPenicillin-binding proteinsGreat promiseAureus
2013
Erratum to: Design, synthesis, in vitro cytotoxicity evaluation and structure–activity relationship of Goniothalamin analogs
Mohideen M, Zulkepli S, Nik-Salleh N, Leong L, Chan K, Inayat-Hussain S, Zulkefeli M, Weber J, Rahman A. Erratum to: Design, synthesis, in vitro cytotoxicity evaluation and structure–activity relationship of Goniothalamin analogs. Archives Of Pharmacal Research 2013, 36: 918-918. DOI: 10.1007/s12272-013-0136-0.Peer-Reviewed Original ResearchStructure-activity relationshipsGoniothalamin analoguesVitro cytotoxicity evaluationCytotoxicity evaluation
2010
Design and synthesis of nonpeptidic, small molecule inhibitors for the Mycobacterium tuberculosis protein tyrosine phosphatase PtpB
Rawls KA, Grundner C, Ellman JA. Design and synthesis of nonpeptidic, small molecule inhibitors for the Mycobacterium tuberculosis protein tyrosine phosphatase PtpB. Organic & Biomolecular Chemistry 2010, 8: 4066-4070. PMID: 20644889, PMCID: PMC3009555, DOI: 10.1039/c0ob00182a.Peer-Reviewed Original ResearchCytotoxic and antioxidant effects of methoxylated stilbene analogues on HepG2 hepatoma and Chang liver cells: Implications for structure activity relationship
Hasiah A, Ghazali A, Weber J, Velu S, Thomas N, Inayat Hussain S. Cytotoxic and antioxidant effects of methoxylated stilbene analogues on HepG2 hepatoma and Chang liver cells: Implications for structure activity relationship. Human & Experimental Toxicology 2010, 30: 138-144. PMID: 20385705, DOI: 10.1177/0960327110368739.Peer-Reviewed Original ResearchConceptsChang liver cellsHepG2 hepatomaTotal antioxidant activityLiver cellsCytotoxic effectsAntioxidant activityFerric Reducing Antioxidant Power AssayChemopreventive activityAntioxidant effectsAntioxidant power assayStilbene analoguesSelective antiproliferative agentsStructure-activity relationship studiesHepG2 cellsAntiproliferative agentsHighest antioxidant activityPower assayHepatomaActivity relationship studiesStructural activity relationshipCytotoxicCellsActivity relationshipsRelationship studiesStructure-activity relationships
2009
Fragment-based discovery of selective inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase PtpA
Rawls KA, Lang PT, Takeuchi J, Imamura S, Baguley TD, Grundner C, Alber T, Ellman JA. Fragment-based discovery of selective inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase PtpA. Bioorganic & Medicinal Chemistry Letters 2009, 19: 6851-6854. PMID: 19889539, PMCID: PMC2801607, DOI: 10.1016/j.bmcl.2009.10.090.Peer-Reviewed Original Research
2003
Curariform Antagonists Bind in Different Orientations to Acetylcholine-binding Protein*
Gao F, Bern N, Little A, Wang HL, Hansen SB, Talley TT, Taylor P, Sine SM. Curariform Antagonists Bind in Different Orientations to Acetylcholine-binding Protein*. Journal Of Biological Chemistry 2003, 278: 23020-23026. PMID: 12682067, PMCID: PMC3191914, DOI: 10.1074/jbc.m301151200.Peer-Reviewed Original ResearchConceptsAcetylcholine-binding proteinDocking orientationTrp-53Site residuesSubunit interfaceLigand bindingProtein flexibilityAChBPNicotinic acetylcholine receptorsSide chainsTyr-89Binding sitesMutagenesisReceptor binding sitesAcetylcholine receptorsProteinSimilar ligandsDynamic structureBindingStructure-activity relationshipsMolecular dynamics simulationsEquivalent nitrogenComputational methodsStructural levelDistinct orientations
1999
Solution structure of neuromedin B by 1H nuclear magnetic resonance spectroscopy
Lee S, Kim Y. Solution structure of neuromedin B by 1H nuclear magnetic resonance spectroscopy. FEBS Letters 1999, 460: 263-269. PMID: 10544247, DOI: 10.1016/s0014-5793(99)01346-0.Peer-Reviewed Original ResearchConceptsNuclear magnetic resonance spectroscopySDS micellesMagnetic resonance spectroscopyTwo-dimensional nuclear magnetic resonance spectroscopyResonance spectroscopyAromatic ring protonsSolution structureMembrane-mimicking environmentHydrophobic acyl chainsStructure-activity relationshipsMethylene protonsLongitudinal relaxation dataNOESY experimentsHelical conformationConformational featuresRing protonsMicellesMolecular mechanismsSpectroscopyAcyl chainsExtrinsic interactionsRelaxation dataEfficient drugsResiduesProtons
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