2025
Molecular insights into de novo small-molecule recognition by an intron RNA structure
Liu T, Xu L, Chung K, Sisto L, Hwang J, Zhang C, Van Zandt M, Pyle A. Molecular insights into de novo small-molecule recognition by an intron RNA structure. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2502425122. PMID: 40339124, PMCID: PMC12088405, DOI: 10.1073/pnas.2502425122.Peer-Reviewed Original ResearchConceptsChemical bonds specificityExperimental structure-activity relationshipsRNA-targeting ligandsIdentification of hitsStructure-activity relationshipRNA-ligand recognitionSmall molecule recognitionSmall molecule bindingMedicinal chemistryHigh-resolution cryoEM structuresMetal ionsHigh-throughput screeningLigand statesRNA structureRNA conformationSplicing inhibitorsRNA targetsCryoEM structureMolecular interactionsDruggable genomeIntronStructural biologyMolecular insightsBond specificityDynamic response
2024
Development of Brain Penetrant Pyridazine Pantothenate Kinase Activators
Tangallapally R, Subramanian C, Yun M, Edwards A, Sharma L, Yang L, Creed K, Wang J, Jackowski S, Rock C, White S, Lee R. Development of Brain Penetrant Pyridazine Pantothenate Kinase Activators. Journal Of Medicinal Chemistry 2024, 67: 14432-14442. PMID: 39136313, PMCID: PMC11345825, DOI: 10.1021/acs.jmedchem.4c01211.Peer-Reviewed Original ResearchConceptsCoA levelsAcyl-CoA levelsIncreased CoA levelsBiosynthesis pathwayPantothenate kinaseStructure-guided designCoA biosynthesisPropionic acidemiaCoenzyme APantothenate kinase-associated neurodegenerationSmall molecule activationCultured cellsBiosynthesisMolecule activationStructure-activity relationshipEnzymeActivation potentialPharmacokinetic profilePhosphopantothenateClinical testingPanKCoAKinaseMetabolic stabilityIsoformsEnantioselective Sulfonimidamide Acylation via a Cinchona Alkaloid-Catalyzed Desymmetrization: Scope, Data Science, and Mechanistic Investigation
Haas B, Lim N, Jermaks J, Gaster E, Guo M, Malig T, Werth J, Zhang H, Toste F, Gosselin F, Miller S, Sigman M. Enantioselective Sulfonimidamide Acylation via a Cinchona Alkaloid-Catalyzed Desymmetrization: Scope, Data Science, and Mechanistic Investigation. Journal Of The American Chemical Society 2024, 146: 8536-8546. PMID: 38480482, PMCID: PMC10990064, DOI: 10.1021/jacs.4c00374.Peer-Reviewed Original ResearchConceptsDensity functional theoryStructure-activity relationshipBis-acylationExcellent yieldsAsymmetric acylationTetrahedral intermediateSynthetic chemistryFunctional theoryMechanistic investigationsReaction kineticsMechanistic studiesSulfonimidamidesDesymmetrizationEnantioselectivityStructural studiesCatalystAcylPharmacophoreCinchonaIntermediateReactionChemistryKineticsYieldReaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase
Xie S, Wang Y, Morton C, Metcalfe R, Dogovski C, Pasaje C, Dunn E, Luth M, Kumpornsin K, Istvan E, Park J, Fairhurst K, Ketprasit N, Yeo T, Yildirim O, Bhebhe M, Klug D, Rutledge P, Godoy L, Dey S, De Souza M, Siqueira-Neto J, Du Y, Puhalovich T, Amini M, Shami G, Loesbanluechai D, Nie S, Williamson N, Jana G, Maity B, Thomson P, Foley T, Tan D, Niles J, Han B, Goldberg D, Burrows J, Fidock D, Lee M, Winzeler E, Griffin M, Todd M, Tilley L. Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase. Nature Communications 2024, 15: 937. PMID: 38297033, PMCID: PMC10831071, DOI: 10.1038/s41467-024-45224-z.Peer-Reviewed Original ResearchConceptsX-ray crystallographic studiesStructure-activity relationshipSynthetically accessible scaffoldMass spectrometryTargeted Mass SpectrometryAccessible scaffoldInhibitor adductX-rayMechanism of actionAmino acid starvation responseMammalian cell toxicityPro inhibitorsAdductsLow mammalian cell toxicityParasite culturesDeploying drugsInhibitor classCell toxicityReactionPlasmodiumResistance developmentLow propensityIncreased resistanceInhibitionSpectrometry
2021
Green Synthesis, Antioxidant, and Plant Growth Regulatory Activities of Novel α‑Furfuryl-2-alkylaminophosphonates
Nadiveedhi M, Nuthalapati P, Gundluru M, Yanamula M, Kallimakula S, Pasupuleti V, Avula V, Vallela S, Zyryanov G, Balam S, Cirandur S. Green Synthesis, Antioxidant, and Plant Growth Regulatory Activities of Novel α‑Furfuryl-2-alkylaminophosphonates. ACS Omega 2021, 6: 2934-2948. PMID: 33553912, PMCID: PMC7860093, DOI: 10.1021/acsomega.0c05302.Peer-Reviewed Original ResearchPlant growth regulatory activityQuantitative structure-activity relationshipKabachnik-Fields reactionStructure-activity relationshipGreen chemical approachGrowth regulatory activityTitle compoundIsolated yieldsSchiff baseMicrowave irradiationMolecular dockingChemical approachSilica gelAmino acid residuesGreen synthesisAcid residuesCompoundsEco-friendlyBioactivity studiesAntioxidant agentsChain CPlantsDialkylphosphitesADMETChain
2014
Chapter 2 Lead Discovery and Lead Modification
Silverman R, Holladay M. Chapter 2 Lead Discovery and Lead Modification. 2014, 19-122. DOI: 10.1016/b978-0-12-382030-3.00002-7.Peer-Reviewed Original ResearchLead compoundsDetermination of structure-activity relationshipsProperties of lead compoundsStages of drug discoveryFragment-based approachConcepts of organic chemistryStructure-activity relationshipVirtual screeningLead discoveryADME propertiesOrganic chemistryGraphics-based methodDrug discoveryCompoundsOral bioavailabilityPharmacophoreComputational methodsPropertiesModification stageChemistryADMELead
2008
Identification of higenamine in Radix Aconiti Lateralis Preparata as a beta2-adrenergic receptor agonist
Bai G, Yang Y, Shi Q, Liu Z, Zhang Q, Zhu Y. Identification of higenamine in Radix Aconiti Lateralis Preparata as a beta2-adrenergic receptor agonist. Acta Pharmacologica Sinica 2008, 29: 1187-1194. PMID: 18817623, DOI: 10.1111/j.1745-7254.2008.00859.x.Peer-Reviewed Original ResearchConceptsRadix Aconiti Lateralis PreparataChinese hamster ovaryAdenosine monophosphateBeta2-adrenergic receptor agonistExperimental asthma modelPeriod of asthmaCyclic adenosine monophosphateBeta2-adrenergic receptorStructure-activity relationshipB2-ARGreen fluorescent protein reporter geneReceptor agonistsFluorescent protein reporter geneIn vivo studiesAsthma modelHigh-performance liquid chromatographic fractionsLiquid chromatographic fractionationAgonistsGuinea pigsMass spectrometryReporter geneHamster ovaryBioactivity-directed fractionationActive compoundsCompounds
2006
Discovery of N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an Agonist of the α7 Nicotinic Acetylcholine Receptor, for the Potential Treatment of Cognitive Deficits in Schizophrenia: Synthesis and Structure−Activity Relationship
Wishka D, Walker D, Yates K, Reitz S, Jia S, Myers J, Olson K, Jacobsen E, Wolfe M, Groppi V, Hanchar A, Thornburgh B, Cortes-Burgos L, Wong E, Staton B, Raub T, Higdon N, Wall T, Hurst R, Walters R, Hoffmann W, Hajos M, Franklin S, Carey G, Gold L, Cook K, Sands S, Zhao S, Soglia J, Kalgutkar A, Arneric S, Rogers B. Discovery of N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an Agonist of the α7 Nicotinic Acetylcholine Receptor, for the Potential Treatment of Cognitive Deficits in Schizophrenia: Synthesis and Structure−Activity Relationship. Journal Of Medicinal Chemistry 2006, 49: 4425-4436. PMID: 16821801, DOI: 10.1021/jm0602413.Peer-Reviewed Original ResearchMeSH Keywordsalpha7 Nicotinic Acetylcholine ReceptorAnimalsBiological AvailabilityBrainBridged Bicyclo Compounds, HeterocyclicCognition DisordersDrug StabilityEther-A-Go-Go Potassium ChannelsEvoked Potentials, AuditoryHumansIn Vitro TechniquesLearningMaleMemoryMicrosomes, LiverNeuronsNicotinic AgonistsNootropic AgentsPatch-Clamp TechniquesQuinuclidinesRadioligand AssayRatsRats, Sprague-DawleyReceptors, NicotinicRecognition, PsychologySchizophreniaStereoisomerismStructure-Activity RelationshipConceptsTreatment of cognitive deficitsPotential treatment of cognitive deficitsExcellent in vitro profileStructure-activity relationshipCognitive deficitsAlpha7 neuronal nicotinic acetylcholine receptorNicotinic acetylcholine receptorsCompound 14Novel object recognitionStructure-activityAuditory sensory gatingAssess cognitive performanceNeuronal nicotinic acetylcholine receptorsAlpha7 nAChR agonistAcetylcholine receptorsSensory gatingCognitive performanceNAChR agonistsPotential treatmentCompoundsAlpha7 nAChRsObject recognitionHigh oral bioavailabilitySchizophreniaBrain penetration
2004
Chapter 2 Drug Discovery, Design, and Development
Silverman R. Chapter 2 Drug Discovery, Design, and Development. 2004, 7-120. DOI: 10.1016/b978-0-08-051337-9.50007-9.Peer-Reviewed Original ResearchDrug designQuantitative structure-activity relationshipQuantitative drug designStructure-activity relationshipDrug discoveryOverview of drug discoverySteric effectsMedicinal chemistsLead compoundsDesign parametersDesignCompoundsRational approachTransport characteristicsMetabolic fatePharmacophorePhysicochemical parametersExpensive processTime-consumingChemistsMoleculesTransportBiological propertiesAverage costCost
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