Voluntary Faculty
Voluntary faculty are typically clinicians or others who are employed outside of the School but make significant contributions to department programs at the medical center or at affiliate institutions.
Voluntary rank detailsRichard Silverman, MD
Assistant Clinical ProfessorAbout
Research
Publications
2026
Inactivation of ornithine aminotransferase by (1R,4S)-4-Amino-3-(trifluoromethyl)cyclopent-2-ene-1-carboxylic acid via a stable quinonoid intermediate
Kang K, Vargas A, Zhu W, Sokolenko I, Liu D, Silverman R. Inactivation of ornithine aminotransferase by (1R,4S)-4-Amino-3-(trifluoromethyl)cyclopent-2-ene-1-carboxylic acid via a stable quinonoid intermediate. Medicinal Chemistry Research 2026, 1-12. DOI: 10.1007/s00044-026-03538-1.Peer-Reviewed Original ResearchStable quinonoid intermediateOrnithine aminotransferasePyridoxal 5'-phosphate (PLP)-dependent enzymeQuinonoid intermediatePLP-dependent enzymesHuman ornithine aminotransferaseGABA-ATX-ray crystallographyCo-inactivationUV–vis spectroscopyHuman OATsGlutamine supplyCancer cellsUV–visInactivationMechanistic pathwaysEnzymeX-rayInactivation pathwayPathwayActive moleculesTargeting Conformational Flexibility of a Reactive Intermediate to Enhance Selectivity of a GABA Aminotransferase Inactivator
Kang K, Vargas A, Ferreira L, Soye B, Corrigan M, Zhang C, Wang F, Duan D, Kelleher N, Hohmann A, Liu D, Silverman R. Targeting Conformational Flexibility of a Reactive Intermediate to Enhance Selectivity of a GABA Aminotransferase Inactivator. Journal Of The American Chemical Society 2026, 148: 8736-8748. PMID: 41711325, PMCID: PMC12927612, DOI: 10.1021/jacs.5c21138.Peer-Reviewed Original ResearchConceptsMechanism-based inactivationGABA-ATReactive intermediatesConformational flexibilityX-ray crystallographyProof-of-concept moleculeCrystal structureAddition pathwayOff-target activityCovalent adductsX-rayConformational transitionIntermediateAdductsHuman ornithine aminotransferaseCPP-115Mechanistic stagesPhase I clinical trialPain animal modelsGeneral design principlesOrnithine aminotransferaseCrystallographyTherapeutic optionsTherapeutic efficacyEnhancement of Potency and Selectivity of 2‑Aminoquinoline-Based Human Neuronal Nitric Oxide Synthase Inhibitors
Ansari A, Kang K, Li H, Hardy C, Rathnayake A, Awasthi A, Poulos T, Silverman R. Enhancement of Potency and Selectivity of 2‑Aminoquinoline-Based Human Neuronal Nitric Oxide Synthase Inhibitors. Journal Of Medicinal Chemistry 2026, 69: 3779-3795. PMID: 41635994, PMCID: PMC12926790, DOI: 10.1021/acs.jmedchem.5c01679.Peer-Reviewed Original ResearchConceptsMolecular dynamics simulationsEnhancement of potencyFavorable solvationLoss of activityHuman neuronal nitric oxide synthasePAMPA-BBBNeuronal nitric oxide synthaseAmino groupsDynamics simulationsIsoform selectivityNeuronal nitric oxide synthase inhibitorPharmacokinetic studiesCompoundsEndothelial NOSInducible NOSDrug potentialNitric oxide synthase inhibitorBrain penetrationSolvationNitric oxide synthasePotencySystemic exposureDerivativesSelectionSuboptimal potencyPotent, Selective, and Brain Penetrant Ether-Linked 2‑Aminopyridine Inhibitors of Human Neuronal Nitric Oxide Synthase with Excellent Oral Bioavailability
Ansari A, Chrzanowski R, Li H, Hardy C, Awasthi A, Poulos T, Silverman R. Potent, Selective, and Brain Penetrant Ether-Linked 2‑Aminopyridine Inhibitors of Human Neuronal Nitric Oxide Synthase with Excellent Oral Bioavailability. Journal Of Medicinal Chemistry 2026, 69: 3506-3518. PMID: 41630196, PMCID: PMC13001636, DOI: 10.1021/acs.jmedchem.5c03568.Peer-Reviewed Original ResearchConceptsOral bioavailabilityHuman neuronal nitric oxide synthaseX-ray crystal structureExcellent oral bioavailabilityNeuronal nitric oxide synthaseArtificial membrane permeability assayParallel Artificial Membrane Permeability AssayEther linkerMembrane permeability assayCrystal structureHuman endothelial NOSBioavailabilityBinding interactionsIsoform selectivityNitric oxide synthaseX-rayPharmacokinetic evaluationBlood-brain barrier penetrationEndothelial NOSOxide synthaseNeuronal nitric oxide synthase inhibitorCompoundsBlood-brain barrierBrain penetrationPermeability assayNew Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma
Awasthi A, Patel A, Li H, Kang K, Hardy C, Ansari A, Nowar R, Hasan E, Yang S, Poulos T, Silverman R. New Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma. Journal Of Medicinal Chemistry 2026, 69: 2310-2329. PMID: 41615895, PMCID: PMC12895717, DOI: 10.1021/acs.jmedchem.5c02154.Peer-Reviewed Original ResearchConceptsNeuronal nitric oxide synthaseNeuronal nitric oxide synthase inhibitionNew inhibitorsX-ray crystallographyNitric oxide synthaseStructure-based approachCases of invasive melanomaOxide synthaseNNOS inhibitorNeuronal nitric oxide synthase inhibitorNNOS selectivityInhibitor of neuronal nitric oxide synthaseTreatment of melanomaMolecular modelingX-rayHuman eNOSInvasive melanomaMelanoma treatmentMelanoma progressionNOS isoformsMelanomaOff-target effectsRat neuronal nitric oxide synthaseAntimelanoma activityNitric oxide
2025
Identification of a glia‐associated amyloid β oligomer subtype and the rescue from reactive astrogliosis by inhibitor NU‐9
Kranz D, de Leon Velez O, Ulupinar E, Ozdinler P, Silverman R, Klein W. Identification of a glia‐associated amyloid β oligomer subtype and the rescue from reactive astrogliosis by inhibitor NU‐9. Alzheimer's & Dementia 2025, 21: e70968. PMID: 41410237, PMCID: PMC12712868, DOI: 10.1002/alz.70968.Peer-Reviewed Original ResearchConceptsIn vivo efficacyDegenerating neuronsReactive astrogliosisReactive astrocytesAstrocyte surfaceImmune cell activationGlial fibrillary acidic proteinPTDP-43Dense depositsFibrillary acidic proteinOral treatmentOld miceStages of degenerationEarly stages of degenerationCell activationNeuronal degenerationNeuronal deathSixty-dayAmyloid-beta oligomersBrain sectionsMicrogliaAstrocytesABONeuronsAlzheimer's diseaseModifications of NU-9, a potent protein aggregation inhibitor. Properties and activity in a cellular model of amyotrophic lateral sclerosis
Elmansy M, Soares P, dos Remedios J, Nowar R, Fox S, Yu A, Klein W, Morimoto R, Silverman R. Modifications of NU-9, a potent protein aggregation inhibitor. Properties and activity in a cellular model of amyotrophic lateral sclerosis. Bioorganic Chemistry 2025, 167: 109190. PMID: 41223590, PMCID: PMC12648443, DOI: 10.1016/j.bioorg.2025.109190.Peer-Reviewed Original ResearchConceptsSmall molecule derivativeAmyotrophic lateral sclerosisCyclohexane-1,3-dioneAmyotrophic Lateral Sclerosis Animal ModelsProtein aggregationCellular modelModel of amyotrophic lateral sclerosisIn vitro BBB permeabilityAnti-aggregative potencyFast-progressing diseaseCellular models of amyotrophic lateral sclerosisEfficacy in vivoIn vitro anti-aggregating activityIn vivo efficacyPathological protein aggregatesPresence of protein aggregatesRespiratory failureMicrosomal stabilityLateral sclerosisProtein aggregation inhibitorsToxicity profileFamilial ALS mutationsAnimal modelsBBB permeabilityAnti-aggregation activityKinetically Controlled aza-Michael/Epimerization Cascade Enables a Scalable Total Synthesis of Putative (+)‑Fumigaclavine F
Dukes A, Weerawarna P, Silverman R. Kinetically Controlled aza-Michael/Epimerization Cascade Enables a Scalable Total Synthesis of Putative (+)‑Fumigaclavine F. Organic Letters 2025, 27: 10174-10179. PMID: 40864606, PMCID: PMC12459949, DOI: 10.1021/acs.orglett.5c03284.Peer-Reviewed Original ResearchTargeting Neuronal Nitric Oxide Synthase (nNOS) as a Novel Approach to Enhancing the Anti-Melanoma Activity of Immune Checkpoint Inhibitors
Patel A, Tong S, Lozada K, Awasthi A, Silverman R, Totonchy J, Yang S. Targeting Neuronal Nitric Oxide Synthase (nNOS) as a Novel Approach to Enhancing the Anti-Melanoma Activity of Immune Checkpoint Inhibitors. Pharmaceutics 2025, 17: 691. PMID: 40574005, PMCID: PMC12196278, DOI: 10.3390/pharmaceutics17060691.Peer-Reviewed Original ResearchPeripheral blood mononuclear cellsNeuronal nitric oxide synthaseNeuronal nitric oxide synthase inhibitorActivity of immune checkpoint inhibitorsT cell activationImmune checkpoint inhibitorsAnti-melanoma activityT cellsTargeting nNOSNitric oxide synthaseCheckpoint inhibitorsIFN-gCD8+ PD-1+ T cellsInterleukin-2PD-1+ T cellsEffects of nNOS inhibitionIL-2-secreting T cellsImmune responseMouse peripheral blood mononuclear cellsOxide synthaseAnti-PD-1Immune checkpoint blockadeMelanoma immune responsePD-1 blockadePD-L1 expressionTruncated pyridinylbenzylamines: Potent, selective, and highly membrane permeable inhibitors of human neuronal nitric oxide synthase
Vasu D, Do H, Li H, Hardy C, Poulos T, Silverman R. Truncated pyridinylbenzylamines: Potent, selective, and highly membrane permeable inhibitors of human neuronal nitric oxide synthase. Bioorganic & Medicinal Chemistry 2025, 124: 118193. PMID: 40252563, PMCID: PMC12404148, DOI: 10.1016/j.bmc.2025.118193.Peer-Reviewed Original ResearchConceptsHuman neuronal nitric oxide synthaseArtificial membrane permeability assayMembrane permeability assayMembrane permeable inhibitorCrystal structureSuzuki-Miyaura cross-coupling reactionTetra-n-butylammonium fluorideCross-coupling reactionsIsoform selectivityTetra-n-butylammoniumEfficient synthetic procedureSynthetic procedureTrifluoroacetic acidExcellent potencyRat neuronal nitric oxide synthaseNeuronal nitric oxide synthaseInhibitor designNovel inhibitorsNitric oxide synthasePermeable inhibitorStructural insightsEndothelial nitric oxide synthasePermeability assayInducible nitric oxide synthaseCrystal