Discovery of novel openers of the understudied human drug target Kir6.1
发现正在研究的人类药物靶标 Kir6.1 的新开启子
基本信息
- 批准号:10580933
- 负责人:
- 金额:$ 46.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAgonistAlgorithmsAmericanAmino AcidsAnalgesicsAstrocytesBindingBiologicalBiological AssayCCL2 geneCRSP3 geneCell LineCellsCessation of lifeChemicalsComplexComputer ModelsCoupledCryoelectron MicroscopyCysteineDataDatabasesDrug TargetingElectrophysiology (science)EngineeringFamilyFutureGenomeGunsHelping to End Addiction Long-termHomology ModelingHumanHypersensitivityIon ChannelLeadLibrariesLigandsLinkMAPK8 geneMalignant Bone NeoplasmMapsMembraneMetabolicMethodsModelingMolecular ConformationMolecular TargetMuscleNerveNeuronsNociceptionNociceptorsOutcomeOverdosePainPain managementPharmaceutical PreparationsPhenotypePhosphatidylinositol 4,5-DiphosphatePhosphotransferasesPhysiologicalPinacidilPostoperative PainPostoperative PeriodProbabilityProteinsPublic HealthQuantitative Structure-Activity RelationshipRattusRegulationReportingResolutionRestRewardsRouteServicesSiteSkinSpinalSpinal CordSpinal GangliaStructural ModelsStructureStructure-Activity RelationshipSurgical incisionsTestingThalliumUnited States National Institutes of HealthValidationVehicle crashX-Ray Crystallographyaddictionantagonistassay developmentbasecancer painchemical groupcheminformaticschronic paindrug discoverydruggable targetfallsin silicoin vitro testingin vivoinhibitorinnovationinward rectifier potassium channelnew therapeutic targetnon-opioid analgesicnovelopioid use disorderpain reductionpain sensationpainful neuropathypalmitoylationpatch clamppreclinical studyprescription opioidpublic health emergencyresponsescreeningsmall moleculesuccessthree dimensional structurethree-dimensional modelingvirtualvirtual libraryvirtual model
项目摘要
Project Summary
Drug overdoses now kill more Americans per year than vehicle crash and gun deaths combined. Overdose
is a common outcome of opioid use disorder (OUD), which itself has been suspected to evolve from routine
prescription treatment of pain with opioid medications. This public health crisis has created a need for the
discovery of non-opioid medications to treat pain without eliciting rewarding effects that lead to addiction. New
molecular targets for pain therapies offer the best route towards elusive non-opioid medications to treat certain
kinds of pain, a fact that is recognized by the present FOA, for which this project is proposed. The ATP-
sensitive inward rectifier potassium channel 8 (Kir6.1/KCNJ8) has been linked to the control of postoperative
and cancer pain, but little else is known about this ion channel in the context of pain. Specifically, Kir6.1
openers/agonists may be novel analgesics, but drug-like, selective openers/agonists of any KATP family
channel have never been identified. Kir6.1 is also considered an understudied protein in terms of its validation
as a druggable target generally and is on the list of qualified drug targets for this FOA. We recently investigated
the regulation by palmitoylation of Kir6 channels. Our studies identified a druggable site utilized by the
palmitoylation mechanism, which provides an avenue to discover drug-like, small molecule opener/agonists
of these channels. We proved the principle that we could find selective openers of Kir6.2 by targeting this site
using in silico/virtual library screening (VLS) coupled with electrophysiological testing in engineered cell lines.
Here, we propose to use the same approach to screen for selective, drug-like openers of Kir6.1 and establish
preliminary structure-activity relationships (SAR) between channel opening and specific chemical
determinants in the ligands. Specifically, we will build highly accurate homology models of alternative
conformations of the Kir6.1/SUR2B complex and use ultra-large VLS to find the maximum number of diverse
chemical entities that fit with the target pocket in its agonist, antagonist and unknown conformations (Aim 1).
These conformations will be refined based on the observed activity of hit ligands. We will also develop three
orthogonal assays to test hit compound identified by VLS: a) a thallium flux cellular primary screening assay,
b) patch clamping of Kir6.1 and c) an LPS-stimulated, human astrocyte MCP-1/p-JNK elevation phenotypic
assay (Aim 2). Finally, SAR will be derived for each of the three assays, and a meta-SAR across the three,
which can serve as an advanced starting point for future drug discovery projects, will be inferred using
cheminformatics methods (Deliverable). A specific 3D structural agonist site on KATP channels has not
previously been identified, so this proposal is highly innovative.
项目总结
项目成果
期刊论文数量(0)
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