Developing an integrative bioinformatic approach for the selection of therapeutic targets

化学探针是一种合成的小分子配体，它可以选择性地结合到给定的蛋白质上，从而调节蛋白质在细胞中的功能。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，最好为人类蛋白质组中的每一种蛋白质开发一种化学探针。在现实中，这一目标是无法实现的，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裂缝/口袋的结构，这对于细胞渗透性小分子配体的有效和特异性结合是必要的：不是所有的蛋白质都是可配体的。此外，结合袋必须在结构上是独特的，以便开发选择性结合感兴趣的蛋白质的小分子配体：化学探针只能用于具有足够结构多样性的蛋白质类。

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.