Sui Huan-Yu, Chen Dong, Huang Jia-Ping, Hu Zhe-Ying, Hu Lu, Shi Jie-Hua, Jiang Shao-Liang
College of Pharmaceutic Science, Zhejiang University of Technology, Hangzhou 310032, China.
College of Pharmaceutic Science, Zhejiang University of Technology, Hangzhou 310032, China.
Spectrochim Acta A Mol Biomol Spectrosc. 2025 Feb 5;326:125197. doi: 10.1016/j.saa.2024.125197. Epub 2024 Sep 23.
Approval in 2019 was granted for the highly selective, targeted agent lorlatinib, which primary target is ROS1 and ALK. The purpose of this work was to examine the binding mechanism between lorlatinib (LOR) and HAG employing multispectral and molecular modeling techniques. Fluorescence data demonstrated that LOR quenched HAG fluorescence as a static quenching, interecalated into the hydrophobic cavity of HAG with a moderate affinity. Thermodynamic and competitive experiments pointed out that LOR bound with HAG primarily through hydrogen bonding, hydrophobic, and van der Waals forces. Circular dichroism, three-dimensional and synchronous fluorescence spectroscopic studies noted that the secondary structure of HAG and microenvironments around tyrosine (Tyr) and tryptophan (Trp) residues were altered due to binding with LOR. The contribution of each energy involved in binding process of LOR and HAG has been analyzed by molecular simulation techniques. Besides, the environmental conditions with metal ions have also been studied. The present study is expected to provide a theoretical basis for further studying the metabolism of LOR in vivo, which may help to gain a deeper understanding of the general pharmacological activity of the drug.
2019年，高选择性靶向药物劳拉替尼获批，其主要靶点为ROS1和ALK。本研究旨在运用多光谱和分子模拟技术研究劳拉替尼（LOR）与HAG之间的结合机制。荧光数据表明，LOR以静态猝灭方式猝灭HAG荧光，以中等亲和力插入HAG的疏水腔。热力学和竞争实验指出，LOR与HAG的结合主要通过氢键、疏水作用和范德华力。圆二色性、三维和同步荧光光谱研究表明，由于与LOR结合，HAG的二级结构以及酪氨酸（Tyr）和色氨酸（Trp）残基周围的微环境发生了改变。通过分子模拟技术分析了LOR与HAG结合过程中各能量的贡献。此外，还研究了金属离子存在下的环境条件。本研究有望为进一步研究LOR在体内的代谢提供理论依据，这可能有助于更深入地了解该药物的一般药理活性。
