Developing an integrative bioinformatic approach for the selection of therapeutic targets

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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.