The recent dissemination of SARS-CoV-2 from Wuhan city to all over the world has created a pandemic. COVID-19 has cost many human lives and created an enormous economic burden. Although many drugs/vaccines are in different stages of clinical trials, still none is clinically available. We have screened a marine seaweed database (1110 compounds) against 3CLpro of SARS-CoV-2 using computational approaches. High throughput virtual screening was performed on compounds, and 86 of them with docking score < − 5.000 kcal mol−1 were subjected to standard-precision docking. Based on binding energies (< − 6.000 kcal mol−1), 9 compounds were further shortlisted and subjected to extra-precision docking. Free energy calculation by Prime-MM/GBSA suggested RC002, GA004, and GA006 as the most potent inhibitors of 3CLpro. An analysis of ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of RC002, GA004, and GA006 indicated that only RC002 (callophysin A, from red alga Callophycus oppositifolius) passed Lipinski’s, Veber’s, PAINS and Brenk’s filters and displayed drug-like and lead-like properties. Analysis of 3CLpro-callophysin A complex revealed the involvement of salt bridge, hydrogen bonds, and hydrophobic interactions. callophysin A interacted with the catalytic residues (His41 and Cys145) of 3CLpro; hence it may act as a mechanism-based competitive inhibitor. Docking energy and docking affinity of callophysin A towards 3CLpro was − 8.776 kcal mol−1 and 2.73 × 106 M−1, respectively. Molecular dynamics simulation confirmed the stability of the 3CLpro-callophysin A complex. The findings of this study may serve as the basis for further validation by in vitro and in vivo studies.

中文翻译：

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筛选藻类代谢产物作为SARS-CoV-2主蛋白酶（3CLpro）的高亲和力抑制剂：计算机模拟分析，以确定对抗COVID-19大流行的新型候选药物

最近，SARS-CoV-2从武汉市向世界各地的传播已引起大流行。COVID-19造成许多人丧生，并造成了巨大的经济负担。尽管许多药物/疫苗处于临床试验的不同阶段，但临床上仍无可用药物。我们使用计算方法筛选了针对SARS-CoV-2的3CLpro的海藻数据库（1110种化合物）。对化合物进行了高通量虚拟筛选，对其中对接得分<-5.000 kcal mol-1的化合物中的86种进行了标准精度对接。根据结合能（<-6.000 kcal mol-1），进一步列出了9种化合物，并进行了超精密对接。Prime-MM / GBSA的自由能计算表明，RC002，GA004和GA006是3CLpro最有效的抑制剂。分析ADMET（吸收，RC002，GA004和GA006的分布，代谢，排泄和毒性特性表明只有RC002（红藻Callophycus oppositifolius的愈伤组织A）通过Lipinski，Veber，PAINS和Brenk的过滤器，并显示出类药物和类铅的特性。对3CLpro-callophysin A的分析表明，盐桥，氢键和疏水相互作用参与其中。愈伤组织A与3CLpro的催化残基（His41和Cys145）相互作用。因此它可以作为基于机制的竞争性抑制剂。愈伤组织A对3CLpro的对接能和对接亲和力分别为-8.776 kcal mol-1和2.73×106 M-1。分子动力学模拟证实了3CLpro-callophysin A复合物的稳定性。