Computer Aided Design of Complement Therapeutics

补体疗法的计算机辅助设计

基本信息

批准号：
7283655
负责人：
JOHN D LAMBRIS
金额：
$ 41.76万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7283655
关键词：
Address Agonist Algorithms Amino Acid Sequence Anaphylatoxin Anaphylatoxins Anti-Inflammatory Agents Anti-inflammatory Area Basic Science Binding Biochemical Biological Assay Biological Process Biology C-terminal Calcium Signaling Cells Chemotaxis Clinic Commit Complement Complement 3a Complement 5a Complement Activation Computer Simulation Computer-Aided Design Computing Methodologies Condition Cyclization Data Drug Delivery Systems Drug Design Elements Enzymes Free Energy Funding Goals Helix (Snails)Hematopoietic Stem Cell Mobilization In Vitro Inflammatory Inflammatory Response Integrins Length Linear Programming Measures Mediator of activation protein Methodology Methods Modeling Modification Muscle Contraction Peptides Phase Pliability Principal Investigator Probability Production Proteins Recording of previous events Research Research Personnel Role Simulate Smooth Muscle Specificity Staging Structure System Testing Therapeutic Therapeutic Uses Validation Vertebral column Work analog base combinatorial complement C3 precursor compstatin computer framework design ear helix improved inhibitor/antagonist interest molecular dynamics novel novel therapeutics phenylalanyl(ornithinyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl)preference programs protein protein interaction research study structural biology therapeutic target

项目摘要

DESCRIPTION (provided by applicant): This is an application for an integrative research effort to design complement therapeutics using computational, physicochemical, and biochemical approaches. The proposed project will accomplish this by bringing together investigators with leading expertise in different fields (complement biology, structural biology, combinatorial and global optimization) who share the same appreciation for the complexity of biological processes and are committed to addressing and elucidating the structural elements involved in protein-protein interactions. The specific contribution of each PI in this project is (i) in silico sequence selection and folding specificity calculations through a novel computational framework that is based on mixed-integer optimization and deterministic global optimization, (ii) in vitro and in silico characterization via NMR, structure determination, and molecular dynamics, and (iii) synthesis and functional characterization of peptides and peptidomimatics to design novel therapeutics. The principal investigators have a long history of scientific interaction that they wish to maintain and expand through the successful funding of this application. Our target is the complement system, and specifically its component C3, and the C3a, and C5a anaphylatoxins. The basis of the proposed work is the recently developed two-stage integrated structural, computational, and experimental protein design method, used not only to select and rank sequences for a particular fold but also to validate the specificity of the fold for these selected sequences. The sequence selection phase relies on flexible templates provided through NMR experiments and analysis, and on an integer linear programming (ILP) model with several constraint modifications that improve the tractability of the problem and enhance its deterministic convergence to the global minimum. In addition, a rank-ordered list of low lying energy sequences are identified, along with the global minimum energy sequence. Once such a subset of sequences have been identified, the fold validation stage is employed to verify the stabilities of the designed sequences through a deterministic global optimization approach that allows for backbone flexibility. The selection of the best designed sequences is based on rigorous quantification of free energy-based probabilities, and it is followed with the experimental validation of structure by NMR and through measuring the complement modulating activities of synthesized compounds. We believe that this methodology is general enough that we expect it will eventually be of broad use in the field of peptide-based drug design.

描述（由申请人提供）：这是一项综合研究工作的应用程序，以使用计算，理化和生化方法来设计补体治疗剂。拟议的项目将通过在不同领域的领先专业知识（补充生物学，结构生物学，组合和全球优化）中汇集研究人员来实现这一目标，他们对生物学过程的复杂性有同样的认识，并致力于解决和阐明与蛋白质蛋白质相互作用相关的结构元素。 The specific contribution of each PI in this project is (i) in silico sequence selection and folding specificity calculations through a novel computational framework that is based on mixed-integer optimization and deterministic global optimization, (ii) in vitro and in silico characterization via NMR, structure determination, and molecular dynamics, and (iii) synthesis and functional characterization of peptides and peptidomimatics to design novel therapeutics.首席研究人员有悠久的科学互动历史，他们希望通过该应用程序的成功资助来维持和扩展。我们的目标是补体系统，特别是其成分C3，以及C3A和C5A过敏毒素。所提出的工作的基础是最近开发的两阶段整合结构，计算和实验蛋白设计方法，不仅用于选择和对特定折叠的序列进行选择和排名序列，还用于验证这些选定序列的折叠特异性。序列选择阶段依赖于通过NMR实验和分析提供的灵活模板，以及具有多种约束修改的整数线性编程（ILP）模型，这些模型可改善问题的障碍性并增强其确定性收敛到全球最小值。此外，确定了低谎言能量序列的等级排序列表，以及全局最小能量序列。一旦确定了这样的序列子集，就会采用折叠验证阶段通过确定性的全局优化方法来验证设计序列的稳定性，该方法允许骨干灵活性。最佳设计序列的选择是基于对基于自由能的概率的严格量化，然后通过NMR和测量合成化合物的补体调节活性对结构进行实验验证。我们认为，这种方法足够笼统，我们希望它最终在基于肽的药物设计领域将被广泛使用。