Dalton Samuel E, Di Pietro Ornella, Hennessy Elisabeth
Department of Discovery Chemistry, MSD, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, United Kingdom.
Department of Discovery Chemistry, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States.
J Med Chem. 2025 Feb 13;68(3):2307-2313. doi: 10.1021/acs.jmedchem.4c02661. Epub 2025 Feb 3.
Covalent modification of disease-driving proteins as a therapeutic strategy has experienced a well-documented resurgence since 2010. However, the earliest FDA approval dates for covalent drugs are in the 1940s, although the covalent mechanism of action may not have been known at the time. This article discloses a data set of all FDA-approved small molecule drugs acting via a covalent mechanism of action, annotated by indication, biological target, reactive group on the drug, biological reactive partner (i.e., amino acid residue, cofactor, etc.), chemical reaction mechanism, bioactivation requirements, key references, and reversibility profile. We discuss these data in the context of addressing key questions posed by the Merck Discovery Chemistry community when considering a chemical series with a covalent mechanism of action.
自2010年以来，将疾病驱动蛋白的共价修饰作为一种治疗策略已出现有充分文献记载的复兴。然而，最早获得美国食品药品监督管理局（FDA）批准的共价药物的日期是在20世纪40年代，尽管当时可能还不知道其共价作用机制。本文披露了所有经FDA批准的通过共价作用机制起作用的小分子药物的数据集，标注有适应症、生物学靶点、药物上的反应基团、生物反应伙伴（即氨基酸残基、辅因子等）、化学反应机制、生物活化要求、关键参考文献和可逆性概况。我们在考虑具有共价作用机制的化学系列时，针对默克发现化学团队提出的关键问题来讨论这些数据。
