Paolino Marco, Tassone Giusy, Governa Paolo, Saletti Mario, Lami Matteo, Carletti Riccardo, Sacchetta Filippo, Pozzi Cecilia, Orlandini Maurizio, Manetti Fabrizio, Olivucci Massimo, Cappelli Andrea
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
Chemistry Department, Bowling Green State University, Overman Hall, Bowling Green, Ohio 43403, United States.
ACS Med Chem Lett. 2025 Feb 28;16(3):397-405. doi: 10.1021/acsmedchemlett.4c00479. eCollection 2025 Mar 13.
The use of Targeted Covalent Inhibitors (TCIs) is an expanding strategy for the development of innovative drugs. It is driven by two fundamental steps: (1) recognition of the target site by the molecule and (2) establishment of the covalent interaction by its reactive group. The development of new TCIs depends on the development of new warheads. Here, we propose the use of Morita-Baylis-Hillman adducts (MBHAs) to covalently bind Lys strategically placed inside a lipophilic pocket. A human cellular retinoic acid binding protein II mutant (M2) was selected as a test bench for a library of 19 MBHAs. The noncovalent interaction step was investigated by molecular docking studies, while experimentally the entire library was incubated with M2 and crystallized to confirm covalent binding with the target lysine. The results, rationalized through covalent docking analysis, support our hypothesis of MBHAs as reactive scaffolds for the design of lysine-TCIs.
靶向共价抑制剂（TCIs）的应用是创新药物研发中不断扩展的策略。它由两个基本步骤驱动：（1）分子对靶点的识别；（2）其反应基团建立共价相互作用。新型TCIs的研发依赖于新型弹头的开发。在此，我们提出使用森田-贝利斯-希尔曼加合物（MBHAs）与策略性地置于亲脂性口袋内的赖氨酸进行共价结合。选择一种人类细胞视黄酸结合蛋白II突变体（M2）作为19种MBHAs文库的测试平台。通过分子对接研究对非共价相互作用步骤进行了研究，而在实验中，将整个文库与M2一起孵育并结晶，以确认与目标赖氨酸的共价结合。通过共价对接分析合理化的结果支持了我们关于MBHAs作为赖氨酸-TCIs设计的反应性支架的假设。
