The predominant existence of covalent modifications of proteins by post-translational modification (PTM) enzymes contributes to the diversity of protein functions, involving greater than 670 modification types on approximately 900000 PTM sites (https://www.uniprot.org/docs/ptmlist.txt). The high dynamic process of PTMs within a cell forms a complex and ever changing nexus of protein modifications, which plays central roles in various cellular signaling functions through different mechanisms, including allosterically regulating enzyme, regulating protein-protein interactions (PPIs), protein localization, degradation, or cleavage. Accumulating evidence has shown that the abnormal status of PTMs is frequently involved in various human diseases, such as cancers, diabetes, and neurodegenerative diseases, making PTMs centrally important for biomarker studies and personalized therapies. Recent advances in different levels of “omics” data have exponentially accelerated the identification of PTM sites. In contrast, PTM functional assignment presents as the bottleneck problem in the modification omics.

Phosphosites Functions

Modern drug design aims to discover novel lead compounds with attractable chemical profiles to enable further exploration of the intersection of chemical space and biological space. Herein, we present a new direction leveraging PTM protein isoforms target space to inspire drug design termed as “PTM Inspired Drug Design (PIDD).”In the biological space, PTM protein isoforms play vitol roles in various diseases and biological signalings. The directions to elaborate PIDD in drug design including discovering covalent binding inhibitors mimicking PTMs, targeting PTM protein isoforms with allosteric sites from that of wildtype counterpart, targeting protein-protein interactions involving PTMs, and hijacking protein degeneration by ubiquitination for PTM protein isoforms. These directions will lead to a significant expansion of the biological space and/or increase the tractability of compounds, primarily due to precisely targeting PTM protein isoforms or complexes which are highly relevant to biological functions. Importantly, this new avenue will further enrich the personalized treatment opportunity through precision medicine targeting PTM isoforms.

Strategies targeting PTM protein isoforms in drug discovery