H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Jamil-ur-Rahman Center for Genome Research, PCMD, ICCBS, University of Karachi, Karachi 75270, Pakistan.
Molecules. 2020 May 12;25(10):2271. doi: 10.3390/molecules25102271.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused about 2 million infections and is responsible for more than 100,000 deaths worldwide. To date, there is no specific drug registered to combat the disease it causes, named coronavirus disease 2019 (COVID-19). In the current study, we used an in silico approach to screen natural compounds to find potent inhibitors of the host enzyme transmembrane protease serine 2 (TMPRSS2). This enzyme facilitates viral particle entry into host cells, and its inhibition blocks virus fusion with angiotensin-converting enzyme 2 (ACE2). This, in turn, restricts SARS-CoV-2 pathogenesis. A three-dimensional structure of TMPRSS2 was built using SWISS-MODEL and validated by RAMPAGE. The natural compounds library Natural Product Activity and Species Source (NPASS), containing 30,927 compounds, was screened against the target protein. Two techniques were used in the Molecular Operating Environment (MOE) for this purpose, i.e., a ligand-based pharmacophore approach and a molecular docking-based screening. In total, 2140 compounds with pharmacophoric features were retained using the first approach. Using the second approach, 85 compounds with molecular docking comparable to or greater than that of the standard inhibitor (camostat mesylate) were identified. The top 12 compounds with the most favorable structural features were studied for physicochemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties. The low-molecular-weight compound NPC306344 showed significant interaction with the active site residues of TMPRSS2, with a binding energy score of -14.69. Further in vitro and in vivo validation is needed to study and develop an anti-COVID-19 drug based on the structures of the most promising compounds identified in this study.
严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）已导致全球约 200 万人感染，并造成超过 10 万人死亡。迄今为止，尚无专门用于对抗该病毒引起的疾病的药物，该疾病被命名为 2019 年冠状病毒病（COVID-19）。在目前的研究中，我们使用了一种基于计算机的方法来筛选天然化合物，以寻找有效的宿主酶跨膜丝氨酸蛋白酶 2（TMPRSS2）抑制剂。这种酶有助于病毒颗粒进入宿主细胞，其抑制作用阻止了病毒与血管紧张素转换酶 2（ACE2）的融合。反过来，这限制了 SARS-CoV-2 的发病机制。使用 SWISS-MODEL 构建了 TMPRSS2 的三维结构，并通过 RAMPAGE 进行了验证。天然化合物库 Natural Product Activity and Species Source（NPASS）包含 30927 种化合物，对目标蛋白进行了筛选。为此，在分子操作环境（MOE）中使用了两种技术，即基于配体的药效团方法和基于分子对接的筛选。总共使用第一种方法保留了具有药效团特征的 2140 种化合物。使用第二种方法，确定了 85 种与标准抑制剂（卡莫司他甲酯）具有可比性或更高分子对接的化合物。研究了具有最有利结构特征的前 12 种化合物的物理化学和 ADMET（吸收、分布、代谢、排泄、毒性）特性。具有低分子量的化合物 NPC306344 与 TMPRSS2 的活性位点残基表现出显著的相互作用，结合能评分为-14.69。需要进一步的体外和体内验证，以研究和开发基于本研究中确定的最有前途的化合物结构的抗 COVID-19 药物。
