Muteeb Ghazala, Alshoaibi Adil, Aatif Mohammad, Rehman Md Tabish, Qayyum M Zuhaib
Department of Nursing, College of Applied Medical Science, King Faisal University, P.O. Box 400, Al-Ahsa, 31982 Saudi Arabia.
Department of Physics, College of Science, King Faisal University, P.O. Box 400, Al-Ahsa, 31982 Saudi Arabia.
Appl Biol Chem. 2020;63(1):79. doi: 10.1186/s13765-020-00564-4. Epub 2020 Nov 21.
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 were subjected to standard-precision docking. Based on binding energies (< - 6.000 kcal mol), 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 ) 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 and 2.73 × 10 M, 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.
近期,严重急性呼吸综合征冠状病毒2(SARS-CoV-2)从武汉市传播至全球,引发了一场大流行。新型冠状病毒肺炎(COVID-19)已导致许多人丧生,并造成了巨大的经济负担。尽管许多药物/疫苗正处于不同阶段的临床试验中,但仍无临床可用的药物。我们使用计算方法,针对SARS-CoV-2的3C样蛋白酶(3CLpro)筛选了一个海洋海藻数据库(1110种化合物)。对化合物进行了高通量虚拟筛选,其中86种对接分数< -5.000千卡/摩尔的化合物进行了标准精度对接。基于结合能(< -6.000千卡/摩尔),进一步筛选出9种化合物并进行高精度对接。通过Prime-MM/GBSA计算自由能表明,RC002、GA004和GA006是3CLpro最有效的抑制剂。对RC002、GA004和GA006的药物代谢动力学(吸收、分布、代谢、排泄和毒性,ADMET)特性分析表明,只有RC002(来自红藻的callophysin A)通过了Lipinski规则、Veber规则、PAINS和Brenk过滤器,并显示出类药物和类先导物的特性。对3CLpro-callophysin A复合物的分析揭示了盐桥、氢键和疏水相互作用的存在。callophysin A与3CLpro的催化残基(His41和Cys145)相互作用;因此,它可能作为一种基于机制的竞争性抑制剂发挥作用。callophysin A对3CLpro的对接能量和对接亲和力分别为-8.776千卡/摩尔和2.73×10 M。分子动力学模拟证实了3CLpro-callophysin A复合物的稳定性。本研究结果可为进一步的体外和体内研究验证提供依据。