Developing an integrative bioinformatic approach for the selection of therapeutic targets

开发用于选择治疗靶点的综合生物信息学方法

• 批准号: RGPIN-2019-04416
• 负责人: Schapira, Matthieu
• 金额: $ 3.06万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=714874
• 关键词: Developing; integrative; bioinformatic; approach; selection

Chemical probes are synthetic small-molecule ligands that bind selectively to a given protein to modulate its function in cell. As such, they are one of the most useful tools to investigate the function of proteins. To systematically explore human biology, a chemical probe should ideally be developed for each protein in the human proteome. In reality, this goal is not attainable as not all proteins have a structure that features crevices/pockets with geometrical and physicochemical properties necessary for the potent and specific binding of a cell-permeable small molecule ligand: not all proteins are ligandable. Additionally, binding pockets must be structurally unique in order to develop small molecule ligands that bind selectively to the protein of interest: chemical probes can only be developed for classes of proteins with sufficient structural diversity. We propose to combine a variety of structural bioinformatic approaches to analyze the chemical tractability of all protein domains (i.e. 3D structural modules) found in the human proteome. 1) We will analyze the atomic 3D structure of protein domains to predict the ligandability of their binding pockets. 2) We will evaluate the structural diversity of binding pockets, an important parameter for the development of selective ligands. We will also analyze the conformational dynamics of protein domains, which has implications for structure--based ligand design and the discovery of allosteric inhibitors. 3) We will combine ligandability, structural diversity, and conformational dynamics properties to draw a chemical tractability landscape of the protein domains, and establish a roadmap to guide emerging large-scale efforts to systematically develop chemical probes for the human proteome, an area of research where Canada is a leader. A longer-term goal will be to expand the analysis to non-human proteomes (including from prokaryotes). Students working on this project will acquire a rare set of expertise in structural bioinformatics, will experience the benefits of adopting open science principles, and will train in a cross-disciplinary, open-concept working environment composed of structural biologists, biochemists, cell biologists. They will also be able to share with and learn from the vibrant local bioinformatics community of downtown Toronto.

化学探针是一种人工合成的小分子配体，它选择性地与给定的蛋白质结合，以调节其在细胞中的功能。因此，它们是研究蛋白质功能的最有用的工具之一。为了系统地探索人类生物学，理想情况下，应该为人类蛋白质组中的每一种蛋白质开发一个化学探针。事实上，这一目标是不可能实现的，因为并不是所有的蛋白质都具有具有几何和物理化学性质的缝隙/口袋结构，这是有效和特定地结合细胞渗透性小分子配体所必需的：并不是所有的蛋白质都是可配基的。此外，结合口袋必须在结构上是独特的，以便开发选择性地与感兴趣的蛋白质结合的小分子配体：化学探针只能针对具有足够结构多样性的一类蛋白质开发。 我们建议结合各种结构生物信息学方法来分析在人类蛋白质组中发现的所有蛋白质结构域(即3D结构模块)的化学可操作性。1)我们将分析蛋白质结构域的原子3D结构，以预测其结合口袋的配位性。2)我们将评估结合口袋的结构多样性，这是开发选择性配体的重要参数。我们还将分析蛋白质结构域的构象动力学，这对基于结构的配体设计和变构抑制剂的发现具有重要意义。3)我们将结合配位性、结构多样性和构象动力学性质来绘制蛋白质结构域的化学可处理性图景，并建立一个路线图，以指导新出现的大规模努力，系统地开发人类蛋白质组的化学探针，这是加拿大处于领先地位的研究领域。一个较长期的目标将是将分析扩大到非人类蛋白质组(包括原核生物)。 从事这个项目的学生将获得一套难得的结构生物信息学专业知识，将体验采用开放科学原则的好处，并将在由结构生物学家、生物化学家和细胞生物学家组成的跨学科、开放概念的工作环境中接受培训。他们还将能够与多伦多市中心充满活力的当地生物信息学社区分享和学习。