High Throughput and Virtual Screening for Human 12-LO, 15-LO-1, and 15-LO-2 Inhib
人类 12-LO、15-LO-1 和 15-LO-2 抑制物的高通量和虚拟筛选
基本信息
- 批准号:7368412
- 负责人:
- 金额:$ 2.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-08-31 至 2009-01-31
- 项目状态:已结题
- 来源:
- 关键词:AnimalsArachidonate 12-LipoxygenaseArachidonate 15-LipoxygenaseArachidonate 5-LipoxygenaseArachidonic AcidsBindingBiological AssayBiological FactorsBiologyBlood PlateletsCell LineCellsChemicalsCollaborationsCollectionComputer AnalysisComputer SimulationDataDiseaseDockingEnzymesFlavonoidsGenomicsGerminationGrantHomology ModelingHormonesHousingHumanInflammatoryInhibitory Concentration 50IschemiaIsoenzymesKineticsLeadLeukotrienesLibrariesLipoxinsLipoxygenaseLipoxygenase 1Lipoxygenase 2Lipoxygenase InhibitorsMalignant NeoplasmsMalignant neoplasm of prostateManualsMethodsModelingNeuronsNumbersOrganismPlantsPlayRateReticulocytesRobotRoleScientistScreening ResultScreening procedureSignaling MoleculeSpecificityTechnologyTherapeuticUnited States National Institutes of HealthWorkcaN protocolcancer cellcostdesigndrug discoveryhigh throughput screeninghuman diseasehuman tissueimprovedin vivoinhibitor/antagonistnovelrepositorysenescencesmall moleculevirtual
项目摘要
DESCRIPTION (provided by applicant): High-throughput screening (HTS) is a major method in early drug discovery and has yet to be fully applied to all human lipoxygenase (hLO) isozymes, critical enzymes in the progression of a number of human diseases. We have currently discovered over 20 novel inhibitors against human lipoxygenase primarily utilizing manual screening but have recently developed a high-throughput assay to increase the rate of discovery. We would now like to apply this HTS technology to the approximately 73,000 compounds at the NIH DPISMR to identify specific inhibitors to each of our three LO isozymes (12- hLO, 15-hLO-1 and 15-hLO-2). The specific inhibitors we discover will then be screened against specific cell lines to determine their in-vivo activity against prostate cancer cells and neuronal cells (as ischemia models). In parallel with the HTS, and at no extra cost to the NIH, we will dock the full HTS library against our three lipoxygenase homology models (12-hLO, 15-hLO-1 and 15-hLO-2) and compare the docking hits to those found by the HTS assay. This comparison will allow us to both improve our in silico methods and help us structurally interpret the HTS data we will obtain. Currently, we have shown both the accuracy and the reliability of this screen against a 47 compound flavonoid library and the NCI 3104 compound Mech./Div./Nat.Prod. library. In addition, Anton Simeonov, at NIH Chemical Genomics Center (NCGC), has successfully screened the LOPAC library with the Kalypsys robot and shown known LO inhibitors can be accurately found. Finally, modeling predictions with Prof. Matt Jacobson have already produced inhibitors from earlier screens. All of this data suggests that these aims are not only feasible but highly likely to be successful. Lipoxygenases (LO) are widely distributed throughout the plant and animal kingdoms and play a central role in the biology of these organisms. In plants they are involved in germination and senescence. In human tissue, there are three major human lipoxygenases, 5-, 12-, and 15-LO, whose primary enzymatic difference lies in their positional specificity on arachidonic acid (AA). The products of lipoxygenase are the precursors of hormones, such as leukotrienes and lipoxins, which have been implicated as critical signaling molecules in a variety of inflammatory diseases and cancers. There is currently strong evidence that if scientists can discover potent inhibitors against each specific lipoxygenase isozyme, these may become effective cellular probes and therapeutics against LO. This grant submission proposes to do exactly this for platlet 12-LO, reticulocyte 15-LO-1 and epidermal 15- LO-2.
描述(由申请人提供):高通量筛选(HTS)是早期药物发现的主要方法,尚未完全应用于所有人脂氧合酶(hLO)同工酶,这些同工酶是许多人类疾病进展中的关键酶。我们目前已经发现了20多个新的抑制剂对人类脂氧合酶主要利用人工筛选,但最近开发了一种高通量的测定,以提高发现率。我们现在想将这种HTS技术应用于NIH DPISMR的大约73,000种化合物,以鉴定我们三种LO同工酶(12- hLO,15-hLO-1和15-hLO-2)中每一种的特异性抑制剂。我们发现的特异性抑制剂将针对特定的细胞系进行筛选,以确定它们对前列腺癌细胞和神经元细胞(作为缺血模型)的体内活性。与HTS平行,并且在不增加NIH成本的情况下,我们将针对我们的三种脂氧合酶同源性模型(12-hLO、15-hLO-1和15-hLO-2)对接完整HTS文库,并将对接命中与HTS测定发现的那些进行比较。这种比较将使我们能够改进我们的计算机方法,并帮助我们从结构上解释我们将获得的HTS数据。目前,我们已经显示了针对47种化合物类黄酮文库和NCI 3104化合物Mech./ Div./ Nat.Prod.图书馆此外,美国国立卫生研究院化学基因组学中心(NCGC)的Anton Simeonov已经成功地用Kalypsys机器人筛选了LOPAC文库,并证明可以准确地找到已知的LO抑制剂。最后,与Matt Jacobson教授一起进行的建模预测已经从早期筛选中产生了抑制剂。所有这些数据都表明,这些目标不仅可行,而且很有可能成功。脂氧合酶(LO)广泛分布于植物和动物界,在这些生物体的生物学中起着核心作用。在植物中,它们参与发芽和衰老。在人体组织中,存在三种主要的人脂氧合酶,5-LO、12-LO和15-LO,其主要的酶差异在于它们对花生四烯酸(AA)的位置特异性。脂氧合酶的产物是激素的前体,如白三烯和脂氧素,其在多种炎性疾病和癌症中被认为是关键的信号分子。目前有强有力的证据表明,如果科学家能够发现有效的抑制剂对每一个特定的脂氧合酶同工酶,这些可能成为有效的细胞探针和治疗LO。该资助申请建议对血小板12-LO、网织红细胞15-LO-1和表皮15- LO-2进行准确的研究。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(4)
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Theodore R Holman其他文献
Theodore R Holman的其他文献
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{{ truncateString('Theodore R Holman', 18)}}的其他基金
Discovery of 12/15-lipoxygenase therapeutics for Alzheimer's disease
发现治疗阿尔茨海默病的 12/15-脂氧合酶疗法
- 批准号:
10427370 - 财政年份:2018
- 资助金额:
$ 2.5万 - 项目类别:
Discovery of 12/15-lipoxygenase therapeutics for Alzheimer's disease
发现治疗阿尔茨海默病的 12/15-脂氧合酶疗法
- 批准号:
9789803 - 财政年份:2018
- 资助金额:
$ 2.5万 - 项目类别:
Discovery of 12/15-Lipoxygenase Inhibitors for Alzheimer's Disease
发现治疗阿尔茨海默病的 12/15-脂氧合酶抑制剂
- 批准号:
9763402 - 财政年份:2018
- 资助金额:
$ 2.5万 - 项目类别:
Discovery of Potent 12-Lipoxygenase Inhibitors of Platelet Activation
发现有效的血小板激活 12-脂氧合酶抑制剂
- 批准号:
8746993 - 财政年份:2014
- 资助金额:
$ 2.5万 - 项目类别:
Discovery of Potent 12-Lipoxygenase Inhibitors of Platelet Activation
发现有效的血小板激活 12-脂氧合酶抑制剂
- 批准号:
9151693 - 财政年份:2014
- 资助金额:
$ 2.5万 - 项目类别:
Development of Potent/Selective Lipoxygenase Therapeutics Against Stroke Injury
针对中风损伤的有效/选择性脂氧合酶疗法的开发
- 批准号:
8632065 - 财政年份:2013
- 资助金额:
$ 2.5万 - 项目类别:
Functional and inhibitory studies of human lipoxygenase
人脂氧合酶的功能和抑制研究
- 批准号:
7820039 - 财政年份:2009
- 资助金额:
$ 2.5万 - 项目类别:
NCRR: UCSC Acquisition of a Thermo Electron LTQ-Mass Spectrometer
NCRR:UCSC 采购热电子 LTQ 质谱仪
- 批准号:
7046277 - 财政年份:2006
- 资助金额:
$ 2.5万 - 项目类别:
FUNCTIONAL STUDIES OF HUMAN AND SOYBEAN LIPOXYGENASE
人类和大豆脂氧合酶的功能研究
- 批准号:
2910348 - 财政年份:1997
- 资助金额:
$ 2.5万 - 项目类别:
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