Department of Biotechnology, Manipur University, Manipur 795003, India.
Department of Bioinformatics, School of Earth, Biological and Environmental Sciences, Central University of South Bihar, Gaya, 824236, India.
Curr Pharm Biotechnol. 2021;22(15):2054-2070. doi: 10.2174/1389201022666210127113027.
In December 2019, an outbreak of a pneumonia-like illness, Corona virus disease 2019 (COVID-19), originating from Wuhan, China, was linked to novel coronavirus, now termed SARS-CoV-2. Unfortunately, no effective drugs or vaccines have been reported yet. The main protease (M) remains the most validated pharmacological target for the design and discovery of inhibitors.
The purpose of the study was to find a prospective natural scaffold as an inhibitor for M main protease in SARS-CoV-2 and compare it with repurposed antiviral drugs lopinavir and nelfinavir.
Natural compound libraries were screened for potential scaffold against M main protease. Molecular dynamics simulation, MM-GBSA and principal component analyses of enzyme- ligand complexes were carried out with the top-ranking hits and compared with the repurposed antiviral drugs lopinavir and nelfinavir.
The structure-based virtual screening indicated phenylbenzopyrone of flavonoids as one of the top-ranking scaffolds that have the potential to inhibit the main protease with the Oglycosidic form, performing better than the corresponding aglyconic form. Simulation studies indicated that glycosidic form of flavonoid is a more suitable inhibitor with compounds rutin, procyanidin B6, baicalin and galloylquercetin, demonstrating high affinity and stability, and rutin, emerging as one of the best candidate compounds. Interestingly, rutin was reported to have inhibitory activity against similar protease (3Cprotease of enterovirus A71) and implicated in lung fibrosis.
The present study on flavonoids, possessing a potential scaffold for inhibiting main protease activity for all betacoronavirus is an attempt to provide new and safe drug leads within a reasonably short period.
2019 年 12 月，源自中国武汉的一种类似肺炎的疾病——2019 年冠状病毒病（COVID-19）与新型冠状病毒有关，现在称为 SARS-CoV-2。不幸的是，目前尚未报道有效的药物或疫苗。主蛋白酶（M）仍然是设计和发现抑制剂的最有效的药物靶点。
本研究旨在寻找一种有前途的天然支架作为 SARS-CoV-2 中 M 主蛋白酶的抑制剂，并将其与已重新用于治疗的抗病毒药物洛匹那韦和奈非那韦进行比较。
筛选天然化合物库，寻找针对 M 主蛋白酶的潜在支架。对排名靠前的命中化合物与已重新用于治疗的抗病毒药物洛匹那韦和奈非那韦进行酶-配体复合物的分子动力学模拟、MM-GBSA 和主成分分析。
基于结构的虚拟筛选表明，类黄酮中的苯并吡喃酮是具有抑制主蛋白酶潜力的排名靠前的支架之一，其糖苷形式比相应的苷元形式更有潜力。模拟研究表明，黄酮类化合物的糖苷形式是一种更合适的抑制剂，化合物芦丁、原花青素 B6、黄芩苷和没食子酸槲皮素具有高亲和力和稳定性，芦丁成为最佳候选化合物之一。有趣的是，芦丁已被报道具有抑制类似蛋白酶（肠道病毒 A71 的 3C 蛋白酶）的活性，并与肺纤维化有关。
本研究对类黄酮进行了研究，类黄酮具有抑制所有β冠状病毒主蛋白酶活性的潜在支架，旨在在合理的短时间内提供新的、安全的药物先导物。
