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 -计算化学与生物物理学
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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