PDF(Pubmed)
Abstract：
Type-II transmembrane serine proteases are effective pharmacological targets for host defence against viral entry and in certain cancer cell progressions. These serine proteases cleave viral spike proteins to expose the fusion peptide for cell entry, which is essential to the life cycle of the virus. TMPRSS2 inhibitors can also fight against respiratory viruses that employ them for cell entry. Our study combining virtual screening, all-atom molecular dynamics, and well-tempered metadynamics simulation identifies vicenin-2, neohesperidin, naringin, and rhoifolin as promising TMPRSS2 antagonists. The binding energies obtained are - 16.3, - 15.4, - 13.6, and - 13.8 kcal/mol for vicenin-2, neohesperidin, naringin, and rhoifolin respectively. The RMSD, RMSF, PCA, DCCM, and binding free energy profiles also correlate with the stable binding of these ligands at the active site of TMPRSS2. The study reveals that these molecules could be promising lead molecules for combating future outbreaks of coronavirus and other respiratory viruses.
摘要：
II型跨膜丝氨酸蛋白酶是宿主防御病毒进入和某些癌细胞进展的有效药理学靶标。这些丝氨酸蛋白酶切割病毒刺突蛋白以暴露融合肽用于细胞进入，这对病毒的生命周期至关重要。TMPRSS2抑制剂还可以对抗使用它们进入细胞的呼吸道病毒。我们的研究结合了虚拟筛查，全原子分子动力学,和良好的元动力学模拟识别维琴宁-2，新橙皮苷，柚皮苷,和rhifolin作为有前途的TMPRSS2拮抗剂。对于vicenin-2，新橙皮苷，获得的结合能为-16.3，-15.4，-13.6和-13.8kcal/mol，柚皮苷,和rhifolin分别。RMSD,RMSF,PCA,DCCM,和结合自由能谱也与这些配体在TMPRSS2的活性位点的稳定结合相关。该研究表明，这些分子可能是有希望的铅分子，用于对抗未来冠状病毒和其他呼吸道病毒的爆发。
