Srivastava Rashi, Tripathi Shubham, Unni Sreepoorna, Hussain Arif, Haque Shafiul, Dasgupta Nandita, Singh Vineeta, Mishra Bhartendu N
Department of Biotechnology, Institute of Engineering and Technology, Dr. A.P.J. Abdul Kalam Technical University, Lucknow- 226021, Uttar Pradesh, India.
Department of Life and Environmental Sciences, College of Natural & Health Sciences, Zayed University, P.O. Box 19282, Dubai, United Arab Emirates.
Curr Pharm Des. 2021;27(32):3476-3489. doi: 10.2174/1381612826666201210122726.
The main proteases (Mpro) and Spike Proteins (SP) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) play a major role in viral infection development by producing several non-structural proteins (nsPs) and penetrating the host cells, respectively. In this study, the potential of in silico molecular docking-based drug repositioning approach was exploited for identifying the inhibitors of M and SP of SARS-CoV-2.
A total of 196 compounds, including various US-FDA-approved drugs, vitamins, and their analogs, were docked with M (PDB IDs: 6YB7 and 6Y84), and the top six ligands were further tested for ADME properties, followed by docking with SP (PDB IDs: 6LXT and 6W41).
Out of 196 compounds, binding energy (DE) of Silybin B (6YB7: DE: -11.20 kcal/mol; 6Y84: DE: - 10.18 kcal/mol; 6LXT: DE: -10.47 kcal/mol; 6W41: DE: -10.96 kcal/mol) and Cianidanol (6YB7: DE: -8.85 kcal/mol; 6LXT: DE: -9.36 kcal/mol; 6Y84: DE: -10.02 kcal/mol; 6W41: DE: -9.52 kcal/mol) demonstrated better binding and ADME properties compared with the currently endeavored drugs like Hydroxychloroquine and Lopinavir. Additionally, Elliptinone, Diospyirin, SCHEMBL94263, and Fiboflavin have shown encouraging results. Fiboflavin, an immunity booster, was found to inhibit both the M and spike protein of SARSCoV- 2. It was observed that amino acid residues MET6, ALA7, PHE8, PRO9, ASP295, GLY302, VAL303, and THR304 play significant roles in protein-ligand interactions through hydrogen bonds and Vander Waals forces.
Silybin B and Cianidanol showed excellent binding and ADME properties compared with the currently endeavored drugs and can be exploited as therapeutic options against SARS-CoV-2 infection after experimental validation and clinical trials.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的主要蛋白酶（Mpro）和刺突蛋白（SP）分别通过产生多种非结构蛋白（nsPs）和穿透宿主细胞在病毒感染发展中起主要作用。在本研究中，利用基于计算机模拟分子对接的药物重新定位方法来鉴定SARS-CoV-2的M和SP的抑制剂。
总共196种化合物，包括各种美国食品药品监督管理局（US-FDA）批准的药物、维生素及其类似物，与M（蛋白质数据银行（PDB）编号：6YB7和6Y84）进行对接，对排名前六位的配体进一步测试其吸收、分布、代谢和排泄（ADME）特性，然后与SP（PDB编号：6LXT和6W41）进行对接。
在196种化合物中，水飞蓟宾B（6YB7：结合能（DE）：-11.20千卡/摩尔；6Y84：DE：-10.18千卡/摩尔；6LXT：DE：-10.47千卡/摩尔；6W41：DE：-10.96千卡/摩尔）和紫铆因（6YB7：DE：-8.85千卡/摩尔；6LXT：DE：-9.36千卡/摩尔；6Y84：DE：-10.02千卡/摩尔；6W41：DE：-9.52千卡/摩尔）与目前正在研究的药物如羟氯喹和洛匹那韦相比，表现出更好的结合和ADME特性。此外，椭圆玫瑰树碱、柿皮素、SCHEMBL94263和核黄素也显示出令人鼓舞的结果。核黄素是一种免疫增强剂，被发现可抑制SARS-CoV-2的M和刺突蛋白。据观察，氨基酸残基MET6、ALA7、PHE8、PRO9、ASP295、GLY302、VAL303和THR304通过氢键和范德华力在蛋白质-配体相互作用中起重要作用。
与目前正在研究的药物相比，水飞蓟宾B和紫铆因表现出优异的结合和ADME特性，经实验验证和临床试验后，可作为抗SARS-CoV-2感染的治疗选择。
