Molecular Diversity ( IF 3.9 ) Pub Date : 2020-11-25 , DOI: 10.1007/s11030-020-10150-x Neelutpal Gogoi 1 , Purvita Chowdhury 2 , Ashis Kumar Goswami 1 , Aparoop Das 1, 3 , Dipak Chetia 1 , Bhaskarjyoti Gogoi 4
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Abstract
Although vaccine development is being undertaken at a breakneck speed, there is currently no effective antiviral drug for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. Therefore, the present study aims to explore the possibilities offered by naturally available and abundant flavonoid compounds, as a prospective antiviral drug to combat the virus. A library of 44 citrus flavonoids was screened against the highly conserved Main Protease (Mpro) of SARS-CoV-2 using molecular docking. The compounds which showed better CDocker energy than the co-crystal inhibitor of Mpro were further revalidated by flexible docking within the active site; followed by assessment of drug likeness and toxicity parameters. The non-toxic compounds were further subjected to molecular dynamics simulation and predicted activity (IC50) using 3D-QSAR analysis. Subsequently, hydrogen bonds and dehydration analysis of the best compound were performed to assess the binding affinity to Mpro. It was observed that out of the 44 citrus flavonoids, five compounds showed lower binding energy with Mpro than the co-crystal ligand. Moreover, these compounds also formed H-bonds with two important catalytic residues His41 and Cys145 of the active sites of Mpro. Three compounds which passed the drug likeness filter showed stable conformation during MD simulations. Among these, the lowest predicted IC50 value was observed for Taxifolin. Therefore, this study suggests that Taxifolin, could be a potential inhibitor against SARS-CoV-2 main protease and can be further analysed by in vitro and in vivo experiments for management of the ongoing pandemic.
Graphic abstract
中文翻译：
计算引导鉴定柑橘类黄酮作为 SARS-CoV-2 主要蛋白酶的潜在抑制剂
抽象的
尽管疫苗开发正在以极快的速度进行，但目前尚无有效的抗病毒药物来治疗引起 COVID-19 的严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2)。因此，本研究旨在探索天然丰富的黄酮类化合物作为对抗病毒的前瞻性抗病毒药物的可能性。通过分子对接，针对 SARS-CoV-2 高度保守的主要蛋白酶 (M pro ) 筛选了 44 种柑橘类黄酮文库。通过在活性位点内灵活对接，进一步重新验证了比 M pro共晶抑制剂表现出更好 CDocker 能量的化合物；随后评估药物相似性和毒性参数。使用 3D-QSAR 分析对无毒化合物进行分子动力学模拟并预测活性 (IC 50 )。随后，对最佳化合物进行氢键和脱水分析，以评估与 M pro 的结合亲和力。据观察，在 44 种柑橘类黄酮中，有 5 种化合物与 M pro的结合能低于共晶配体。此外，这些化合物还与M pro活性位点的两个重要催化残基His41和Cys145形成氢键。通过药物相似过滤器的三种化合物在 MD 模拟过程中显示出稳定的构象。其中，观察到紫杉叶素的预测 IC 50值最低。因此，这项研究表明，紫杉醇可能是 SARS-CoV-2 主要蛋白酶的潜在抑制剂，并且可以通过体外和体内实验进一步分析，以管理正在进行的大流行。
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