Mahmudpour Mehdi, Nabipour Iraj, Keshavarz Mohsen, Farrokhnia Maryam
The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran.
The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran.
Front Chem. 2021 Oct 12;9:722633. doi: 10.3389/fchem.2021.722633. eCollection 2021.
Although SARS-CoV-2 entry to cells strictly depends on angiotensin-converting enzyme 2 (ACE2), the virus also needs transmembrane serine protease 2 (TMPRSS2) for its spike protein priming. It has been shown that the entrance of SARS-CoV-2 through ACE2 can be blocked by cellular TMPRSS2 blockers. The main aim of this study was to find potential inhibitor(s) of TMPRSS2 through virtual screening against a homology model of TMPRSS2 using the library of marine natural products (MNPs). The homology modeling technique for generating a three-dimensional structure of TMPRSS2 was applied. Molecular docking, MM-GBSA and absorption, distribution, metabolism, excretion (ADME) evaluations were performed to investigate the inhibitory activity of marine natural products (MNPs) against TMPRSS2 and their pharmacokinetic properties. Camostat and nafamostat mesylate were used as the standard inhibitory molecules. Seven MNPs were able to inhibit TMPRSS2 better than the standard compounds. MNP 10 with CAS number 107503-09-3, called Watasenia β-D- Preluciferyl glucopyrasoiuronic acid, was found to be the best inhibitor of TMPRSS2 with acceptable pharmacokinetic properties. Herein, for the first time, a new marine natural product was introduced with potent inhibitory effects against TMPRSS2. MNP 10 exhibited favorable drug-like pharmacokinetic properties and it promises a novel TMPRSS2 blocker to combat SARS-CoV-2.
尽管严重急性呼吸综合征冠状病毒2（SARS-CoV-2）进入细胞严格依赖血管紧张素转换酶2（ACE2），但该病毒的刺突蛋白激活还需要跨膜丝氨酸蛋白酶2（TMPRSS2）。研究表明，细胞内的TMPRSS2阻滞剂可阻断SARS-CoV-2通过ACE2进入细胞。本研究的主要目的是通过使用海洋天然产物（MNP）文库对TMPRSS2的同源模型进行虚拟筛选，寻找TMPRSS2的潜在抑制剂。应用同源建模技术生成TMPRSS2的三维结构。进行分子对接、MM-GBSA以及吸收、分布、代谢、排泄（ADME）评估，以研究海洋天然产物（MNP）对TMPRSS2的抑制活性及其药代动力学性质。使用抑肽酶和甲磺酸盐那法莫司作为标准抑制分子。七种MNP对TMPRSS2的抑制作用优于标准化合物。发现CAS编号为107503-09-3的MNP 10（称为磷虾β-D-前荧光素基吡喃葡萄糖醛酸）是TMPRSS2的最佳抑制剂，具有可接受的药代动力学性质。在此，首次引入了一种对TMPRSS2具有强效抑制作用的新型海洋天然产物。MNP 10表现出良好的类药物药代动力学性质，有望成为一种新型的TMPRSS2阻滞剂来对抗SARS-CoV-2。
