Singh Sameer, Gangopadhyay Aditi, D Sriram, Chakravarty Manab
Department of Chemistry, Birla Institute of Technology & Science Pilani - Hyderabad Campus, Hyderabad, Telangana, India.
Department of Chemical Technology, University of Calcutta, Kolkata, West Bengal, India.
R Soc Open Sci. 2025 Apr 2;12(4):241628. doi: 10.1098/rsos.241628. eCollection 2025 Apr.
In this report, a structurally unique phenothiazine (PTZ) core is linked with glutamic acid-based dendrons through a solid-phase peptide synthesis approach to access a variety of PTZ-linked dendrons conveniently. Inferior cytotoxicity of anionic surface-linked second-generation glutamic acid-based dendrons would be more desirable for various applications than respective lysine-based dendrons. Solid-phase synthesis of PTZ-linked glutamic acid-based dendrons would be a novel approach to access this class of molecules. These newly synthesized dendrons were screened as an inhibitor against the main protease (M) enzyme, proposed to be the best target against SARS-CoV-2. The preliminary assay studies designated a moderate response for the M inhibition, specifically by tryptophan (Trp)-enriched dendron, among other analogues, which play a vital role in combating COVID-19. Further, the experimental studies realize the essential contribution of the PTZ core in interacting with the M enzyme. Molecular dynamics (MD) simulations revealed that the active dendrons formed stable complexes with M, and the binding affinity of the Trp-based PTZ-linked dendrons was higher than that of the decoy dendron analogue.
在本报告中，一种结构独特的吩噻嗪（PTZ）核心通过固相肽合成方法与基于谷氨酸的树枝状分子相连，从而方便地获得了多种与PTZ相连的树枝状分子。与相应的基于赖氨酸的树枝状分子相比，阴离子表面连接的第二代基于谷氨酸的树枝状分子的较低细胞毒性在各种应用中更具优势。PTZ连接的基于谷氨酸的树枝状分子的固相合成将是获得这类分子的一种新方法。这些新合成的树枝状分子被筛选作为针对主要蛋白酶（M）的抑制剂，该酶被认为是对抗严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的最佳靶点。初步测定研究表明，在其他类似物中，特别是富含色氨酸（Trp）的树枝状分子对M抑制有中等程度的反应，这在对抗2019冠状病毒病（COVID-19）中起着至关重要的作用。此外，实验研究认识到PTZ核心在与M酶相互作用中的重要贡献。分子动力学（MD）模拟表明，活性树枝状分子与M形成稳定的复合物，基于Trp的PTZ连接树枝状分子的结合亲和力高于诱饵树枝状分子类似物。
