Department of Basic Sciences and Social Sciences, North-Eastern Hill University, Shillong, 793022, Meghalaya, India.
Department of Zoology, College of Science, King Saud University, Riyadh,11451, Saudi Arabia.
Curr Pharm Biotechnol. 2022;23(7):959-969. doi: 10.2174/1389201022666210604150041.
There has been tremendous pressure on healthcare facilities globally due to the recent emergence of novel coronavirus infection known as COVID-19 and its rapid spread across the continents. The lack of effective therapeutics for the management of the pandemic calls for the discovery of new drugs and vaccines.
In the present study, a chemical library was screened for molecules against three coronavirus 3CL-like protease enzymes (SARS-CoV-2 3CLpro, SARS-CoV 3CLpro and MERS-CoV 3CLpro), which are a key player in the viral replication cycle.
Extensive computational methods such as virtual screening and molecular docking were employed in this study.
Two lead molecules, ZINC08825480 (4-bromo-N'-{(E)-[1-phenyl-3-(pyridin-3-yl)-1H-pyrazol- 4-yl]methylidene}benzene-1-sulfonohydrazide) and ZINC72009942 (N-[[2-[[(3S)-3-methyl-1-piperidyl] methyl]phenyl]methyl]-6-oxo-1-(p-tolyl)-4,5-dihydro-1,2,4-triazine-3-carboxamide), were identified with better affinity with the three target enzymes as compared to the approved antiviral drugs. Both the lead molecules possessed favorable drug-like properties, fit well into the active site pocket close to His- Cys dyad and showed a good number of hydrogen bonds with the backbone as well as side chains of key amino acid residues.
Thus, the present study offers two novel chemical entities against coronavirus infections which can be validated through various biological assays.
由于新型冠状病毒感染（即 COVID-19）的出现及其在各大洲的迅速传播，全球医疗机构面临巨大压力。目前缺乏有效的治疗方法来应对这一流行病，因此需要开发新的药物和疫苗。
本研究对一个化学文库进行了筛选，以寻找针对三种冠状病毒 3CL 样蛋白酶（SARS-CoV-2 3CLpro、SARS-CoV 3CLpro 和 MERS-CoV 3CLpro）的分子，这些酶是病毒复制周期中的关键因素。
本研究采用了广泛的计算方法，如虚拟筛选和分子对接。
发现了两种先导化合物，ZINC08825480（4-溴-N'-{[1-苯基-3-（3-吡啶基）-1H-吡唑-4-基]亚甲基}苯-1-磺酰基）肼）和 ZINC72009942（N-[[2-[[（3S）-3-甲基-1-哌啶基]甲基]苯基]甲基]-6-氧代-1-（对甲苯基）-4,5-二氢-1,2,4-三嗪-3-甲酰胺），与三种靶酶的亲和力优于已批准的抗病毒药物。这两种先导化合物都具有良好的类药性，与活性口袋中的 His-Cys 二联体接近，与关键氨基酸残基的骨架和侧链形成了大量氢键。
因此，本研究提供了两种针对冠状病毒感染的新型化学实体，可以通过各种生物学测定进行验证。
