Sharma Tanuj, Abohashrh Mohammed, Baig Mohammad Hassan, Dong Jae-June, Alam Mohammad Mahtab, Ahmad Irfan, Irfan Safia
Department of Family Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Basic Medical Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
Saudi J Biol Sci. 2021 May;28(5):3152-3159. doi: 10.1016/j.sjbs.2021.02.059. Epub 2021 Feb 23.
Although several pharmacological agents are under investigation to be repurposed as therapeutic against COVID-19, not much success has been achieved yet. So, the search for an effective and active option for the treatment of COVID-19 is still a big challenge. The Spike protein (S), RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro) are considered to be the primary therapeutic drug target for COVID-19. In this study we have screened the drugbank compound library against the Main Protease. But our search was not limited to just Mpro. Like other viruses, SARS-CoV-2, have also acquired unique mutations. These mutations within the active site of these target proteins may be an important factor hindering effective drug candidate development. In the present study we identified important active site mutations within the SARS-CoV-2 Mpro (Y54C, N142S, T190I and A191V). Further the drugbank database was computationally screened against Mpro and the selected mutants. Finally, we came up with the common molecules effective against the wild type (WT) and all the selected Mpro. The study found Imiglitazar, was found to be the most active compound against the wild type of Mpro. While PF-03715455 (Y54C), Salvianolic acid A (N142S and T190I), and Montelukast (A191V) were found to be most active against the other selected mutants. It was also found that some other compounds such as Acteoside, 4-Amino-N- {4-[2-(2,6-Dimethyl-Phenoxy)-Acetylamino]-3-Hydroxy-1-Isobutyl-5-Phenyl-Pentyl}-Benzamide, PF-00610355, 4-Amino-N-4-[2-(2,6-Dimethyl-Phenoxy)-Acetylamino]-3-Hydroxy-1-Isobutyl-5-Phenyl-Pentyl}-Benzamide and Atorvastatin were showing high efficacy against the WT as well as other selected mutants. We believe that these molecules will provide a better and effective option for the treatment of COVID-19 clinical manifestations.
尽管有几种药物正在进行重新开发以用于治疗新冠肺炎，但目前尚未取得太大成功。因此，寻找一种有效且积极的新冠肺炎治疗方案仍然是一项巨大挑战。刺突蛋白（S）、RNA依赖性RNA聚合酶（RdRp）和主要蛋白酶（Mpro）被认为是新冠肺炎的主要治疗药物靶点。在本研究中，我们针对主要蛋白酶筛选了药物银行化合物库。但我们的搜索并不局限于Mpro。与其他病毒一样，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）也出现了独特的突变。这些靶蛋白活性位点内的突变可能是阻碍有效候选药物开发的重要因素。在本研究中，我们确定了SARS-CoV-2 Mpro（Y54C、N142S、T190I和A191V）内重要的活性位点突变。进一步针对Mpro和选定的突变体对药物银行数据库进行了计算机筛选。最后，我们找到了对野生型（WT）和所有选定的Mpro均有效的共同分子。研究发现，依米格列扎被发现是对野生型Mpro最具活性的化合物。而PF-03715455（Y54C）、丹酚酸A（N142S和T190I）和孟鲁司特（A191V）被发现对其他选定的突变体最具活性。还发现一些其他化合物，如毛蕊花糖苷、4-氨基-N-{4-[2-(2,6-二甲基苯氧基)-乙酰氨基]-3-羟基-1-异丁基-5-苯基戊基}-苯甲酰胺、PF-00610355、4-氨基-N-4-[2-(2,6-二甲基苯氧基)-乙酰氨基]-3-羟基-1-异丁基-5-苯基戊基}-苯甲酰胺和阿托伐他汀对WT以及其他选定的突变体均显示出高效。我们相信这些分子将为治疗新冠肺炎临床表现提供更好且有效的选择。
