Abstract
Proximity-induced pharmacology (ProxPharm) is a novel paradigm in drug discovery where a small molecule brings two proteins in close proximity to elicit a signal, generally from one protein onto another. The potential of ProxPharm compounds as a new therapeutic modality is firmly established by proteolysis targeting chimeras (PROTACs) that bring an E3 ubiquitin ligase in proximity to a target protein to induce ubiquitination and subsequent degradation of the target. The concept can be expanded to induce other post-translational modifications via the recruitment of different types of protein-modifying enzymes. To survey the human proteome for opportunities in proximity pharmacology, we systematically mapped non-catalytic drug binding pockets on the structure of protein-modifying enzymes available from the Protein Databank. In addition to binding sites exploited by previously reported ProxPharm compounds, we identified putative ligandable non-catalytic pockets in 236 kinases, 45 phosphatases, 37 deubiquitinases, 14 methyltransferases, 11 acetyltransferases, 13 glycosyltransferases, 4 deacetylases, 7 demethylases and 2 glycosidases, including cavities occupied by chemical matter that may serve as starting points for future ProxPharm compounds. This systematic survey confirms that proximity pharmacology is a versatile modality with largely unexplored and promising potential and reveals novel opportunities to pharmacologically rewire molecular circuitries. All data is available from the ProxyBind database at https://polymorph.sgc.utoronto.ca/proxybind/index.php.