Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
Med Res Rev. 2021 May;41(3):1701-1750. doi: 10.1002/med.21774. Epub 2020 Dec 23.
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. Identification of small molecules with good ligand efficiency, high activity, and selectivity is crucial toward developing effective and safe drugs. However, the intersection is one of the most challenging tasks in the pharmaceutical industry, as chemical space is almost infinity and continuous, whereas the biological space is very limited and discrete. This bottleneck potentially limits the discovery of molecules with desirable properties for lead optimization. Herein, we present a new direction leveraging posttranslational modification (PTM) protein isoforms target space to inspire drug design termed as "Post-translational Modification Inspired Drug Design (PTMI-DD)." PTMI-DD aims to extend the intersections of chemical space and biological space. We further rationalized and highlighted the importance of PTM protein isoforms and their roles in various diseases and biological functions. We then laid out a few directions to elaborate the PTMI-DD in drug design including discovering covalent binding inhibitors mimicking PTMs, targeting PTM protein isoforms with distinctive binding sites from that of wild-type 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.
现代药物设计旨在发现具有吸引力化学特征的新型先导化合物，以进一步探索化学空间和生物空间的交集。识别具有良好配体效率、高活性和选择性的小分子对于开发有效和安全的药物至关重要。然而，交集是制药行业最具挑战性的任务之一，因为化学空间几乎是无限和连续的，而生物空间非常有限和离散。这个瓶颈可能限制了发现具有理想性质的分子进行先导优化。在此，我们提出了一个新的方向，利用翻译后修饰（PTM）蛋白异构体靶标空间来激发药物设计，称为“翻译后修饰启发的药物设计（PTMI-DD）”。PTMI-DD 的目的是扩展化学空间和生物空间的交集。我们进一步合理化并强调了 PTM 蛋白异构体及其在各种疾病和生物学功能中的作用的重要性。然后，我们提出了几个方向来阐述药物设计中的 PTMI-DD，包括发现模拟 PTM 的共价结合抑制剂、针对与野生型对应物不同的结合位点的 PTM 蛋白异构体、针对涉及 PTM 的蛋白质-蛋白质相互作用、以及通过泛素化劫持 PTM 蛋白异构体的蛋白退化。这些方向将导致生物空间的显著扩展和/或增加化合物的可处理性，主要是由于能够精确地针对与生物学功能高度相关的 PTM 蛋白异构体或复合物。重要的是，这条新途径将通过针对 PTM 异构体的精准医学进一步丰富个性化治疗机会。
