CORE C
核心C
基本信息
- 批准号:10225395
- 负责人:
- 金额:$ 25.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-09 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAntiviral AgentsBRCA1 geneBinding SitesBiochemicalBiologicalBiological AssayBiological TestingBiologyBiophysicsBreastCDK4 geneChemical ModelsChemicalsClinicalCollaborationsComplexComputer ModelsComputing MethodologiesCrystallizationCytosineCytosine deaminaseD CellsDataDeaminationDefectDevelopmentDrug KineticsDrug resistanceEffectivenessEnzymesEstrogen receptor positiveEvolutionExcretory functionGenerationsGoalsGraphInheritedKineticsLengthLigandsMacromolecular ComplexesMalignant NeoplasmsMammary NeoplasmsMetabolismMetastatic breast cancerModelingMolecularMonoclonal AntibodiesMutagenesisMutationNeoplasm MetastasisNucleic AcidsOutcomePIK3CA genePhysiologicalPrimary NeoplasmProcessPropertyProteinsRegulationReportingResolutionRoentgen RaysRoleSingle-Stranded DNASourceStructural ModelsStructureSystemTechniquesTestingThe Cancer Genome AtlasThermodynamicsTimeUracilVertebral columnabsorptionbasebiophysical chemistrybiophysical modelchemical bindingcomputational chemistrydata streamsdesignexperimental studyhomologous recombinationimprovedin silicoin vivoinhibitor/antagonistinnovationinsightlead optimizationmalignant breast neoplasmmodel developmentmolecular dynamicsmolecular recognitionmultidisciplinarynanosecondneoplastic cellnoveloperationpreventprogramsreceptorresistance mutationscreeningsimulationsmall moleculestructural biologythree dimensional structuretumor
项目摘要
CORE C – COMPUTATIONAL CHEMISTRY & BIOPHYSICS
ABSTRACT
APOBEC is a recently discovered enzymatic source of mutation in breast cancer. Multiple lines of evidence
indicate that APOBEC mutagenesis is an ongoing source of mutation in tumor cells and that the major enzyme
responsible is the single-stranded (ss)DNA cytosine deaminase APOBEC3B (A3B). Our Program is therefore
united in testing the overarching hypothesis that A3B inhibition will prevent a large proportion of new mutations
in estrogen receptor-positive breast cancer, thereby improving the durability of current treatments and resulting
in better overall outcomes. Projects 1, 2, and 3 are focused on testing this idea through a carefully organized
multidisciplinary team involving biology, chemical biology, and structural biology approaches. Core C –
Computational Chemistry & Biophysics provides the computational modeling backbone to support these
Projects through 2 well-integrated specific aims. Aim 1 encompasses the development of physically detailed
3D structural models of APOBEC biomolecular systems, including those that prove challenging to resolve
experimentally, such as the different macromolecular regulatory complexes being explored in Project 1, or full-
length, wild-type A3B in complex with ssDNA in Project 3. In these examples and others, explicitly solvated
molecular dynamics (MD) simulations will be used to predict atomic-level interactions, and these dynamic 3-
dimensional models will guide wet experiments by the Project teams. The resulting data will drive Core C to
develop further refined models for additional testing by the Project teams. Aim 2 consists of in silico small
molecule screening and lead optimization. Innovative MD analysis frameworks, such as Markov state modeling,
will be used to extract long-timescale dynamics from many short-timescale simulations and elucidate the
thermodynamic and kinetic landscapes of APOBEC enzymes that control molecular recognition and functional
activity. A key strength of this approach is identification of cryptic pockets that are capable of binding chemical
probes but are often absent from x-ray structures. A range of ligand- and receptor-based approaches will be
employed in silico to increase the diversity of APOBEC inhibitors. Core C will also perform lead optimization in
silico, including computational Absorption Distribution Metabolism Excretion / Pharmacokinetics (ADME/PK)
optimization to help avoid potential chemical liabilities and maximize experimental efficiencies. Inhibitors and
probes will be developed through continual collaboration with Projects 2 and 1 and Core D. The biochemical
and biological testing of candidate molecules identified or predicted in silico will fuel additional rounds of
computational refinement, ultimately leading to structural studies by Project 3 and in vivo tumor evolution
experiments by Core B.
核心C -基础化学和生物物理
摘要
APOBEC是最近发现的乳腺癌突变的酶源。多种证据
表明APOBEC诱变是肿瘤细胞中突变持续来源,
负责的是单链(ss)DNA胞嘧啶脱氨酶APOBEC 3B(A3 B)。因此,我们的计划是
在检验A3 B抑制将阻止大部分新突变的总体假设时,
在雌激素受体阳性乳腺癌中,从而提高了目前治疗的持久性,
更好的整体结果。项目1、2和3的重点是通过精心组织的
涉及生物学、化学生物学和结构生物学方法的多学科团队。核心C -
计算化学与生物物理学提供了计算建模的骨干,以支持这些
通过两个整合良好的具体目标的项目。目标1包括开发物理详细的
APOBEC生物分子系统的3D结构模型,包括那些证明具有挑战性的解决方案
实验上,如项目1中探索的不同大分子调节复合物,或完整的
长度,野生型A3 B与项目3中的ssDNA复合。在这些实施例和其他实施例中,明确溶剂化的
分子动力学(MD)模拟将用于预测原子级相互作用,这些动态3-
三维模型将指导项目团队的湿实验。由此产生的数据将推动核心C,
开发进一步完善的模型,供项目小组进行额外测试。Aim 2由计算机模拟小
分子筛选和先导物优化。创新的MD分析框架,如马尔可夫状态建模,
将用于从许多短时间尺度模拟中提取长时间尺度动力学,并阐明
热力学和动力学景观APOBEC酶控制分子识别和功能
活动这种方法的一个关键优势是识别能够结合化学物质的隐蔽口袋。
探针,但通常不存在于X射线结构中。一系列基于配体和受体的方法将在
在计算机上使用,以增加APOBEC抑制剂的多样性。Core C还将在
计算机模拟,包括计算吸收分布代谢排泄/药代动力学(ADME/PK)
优化,以帮助避免潜在的化学责任和最大限度地提高实验效率。抑制剂和
将通过与项目2和1以及核心D的持续合作开发探测器。生化
对计算机识别或预测的候选分子进行生物学测试将推动更多轮的
计算精细化,最终导致项目3的结构研究和体内肿瘤演变
核心B的实验。
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(0)
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Rommie E Amaro其他文献
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{{ truncateString('Rommie E Amaro', 18)}}的其他基金
Multiscale Computational Microscopy of HIV-1
HIV-1 的多尺度计算显微镜
- 批准号:
10756808 - 财政年份:2023
- 资助金额:
$ 25.83万 - 项目类别:
A MULTISCALE APPROACH TO TARGET THE ACHILLES HEEL OF P53 CANCER MUTANTS
针对 P53 癌症突变体致命弱点的多尺度方法
- 批准号:
10391499 - 财政年份:2019
- 资助金额:
$ 25.83万 - 项目类别:
A MULTISCALE APPROACH TO TARGET THE ACHILLES HEEL OF P53 CANCER MUTANTS
针对 P53 癌症突变体致命弱点的多尺度方法
- 批准号:
9906241 - 财政年份:2019
- 资助金额:
$ 25.83万 - 项目类别:
AN OPEN RESOURCE TO ADVANCE COMPUTER-AIDED DRUG DESIGN
推进计算机辅助药物设计的开放资源
- 批准号:
8756082 - 财政年份:2014
- 资助金额:
$ 25.83万 - 项目类别:
Towards a Structural Systems Biology Approach for Anti-Trypanosomal Therapeutics
抗锥虫治疗的结构系统生物学方法
- 批准号:
7791099 - 财政年份:2010
- 资助金额:
$ 25.83万 - 项目类别:
Towards a Structural Systems Biology Approach for Anti-Trypanosomal Therapeutics
抗锥虫治疗的结构系统生物学方法
- 批准号:
8122149 - 财政年份:2010
- 资助金额:
$ 25.83万 - 项目类别:
A Structural Systems Biology Approach to Drug Discovery
药物发现的结构系统生物学方法
- 批准号:
8798517 - 财政年份:2010
- 资助金额:
$ 25.83万 - 项目类别:
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