[论文解读] In Silico Screening of Some Naturally Occurring Bioactive Compounds Predicts Potential Inhibitors against SARS-COV-2 (COVID-19) Protease

Ashok Kumar Mishra, Satya Prakash Tewari|arXiv (Cornell University)|Apr 3, 2020

Computational Drug Discovery Methods参考文献 15被引用 6

一句话总结

这项体外研究评估了来自 *Anthocephalus cadamba* 的九种天然生物活性化合物对SARS-CoV-2主蛋白酶（Mpro）的潜在抑制作用。采用密度泛函理论（B3LYP/631+G(d,p)）和分子对接方法，齐墩果酸被预测为结合亲和力最高的抑制剂，其次为熊果酸及其他化合物，表明其作为低成本、低毒性抗COVID-19候选药物的潜力，有待体内验证。

ABSTRACT

SARS-COV-2 identified as COVID-19 in Wuhan city of China in the month of December, 2019 has now been declared as pandemic by World Health Organization whose transmission chain and cure both have emerged as a tough problem for the medical fraternity. The reports pertaining to the treatment of this pandemic are still lacking. We firmly believe that Nature itself provides a simple solution for any complicated problem created in it which motivated us to carry out In Silico investigations on some bioactive natural compounds reportedly found in the fruits and leaves of Anthocephalus Cadamba which is a miraculous plant found on the earth aiming to predict the potential inhibitors against aforesaid virus. Having modeled the ground state ligand structure of the such nine natural compounds applying density functional theory at B3LYP/631+G (d, p) level we have performed their molecular docking with SARS-COV-2 protease to calculate the binding affinity as well as to screen the binding at S-protein site during ligand-protein interactions. Out of these nine studied naturally occurring compounds; Oleanic Acid has been appeared to be potential inhibitor for COVID-19 followed by Ursolic Acid, IsoVallesiachotamine,Vallesiachotamine,Cadambine,Vincosamide-N-Oxide, Isodihydroamino-cadambine, Pentyle Ester of Chlorogenic Acid and D-Myo-Inositol. Hence these bioactive natural compounds or their structural analogs may be explored as anti-COVID19 drug agent which will be possessing the peculiar feature of cost-less synthesis and less or no side effect due to their natural occurrence. The solubility and solvent-effect related to the phytochemicals may be the point of concern. The In-vivo investigations on these proposed natural compounds or on their structural analogs are invited for designing and developing the potential medicine/vaccine for the treatment of COVID-19 pandemic.

研究动机与目标

• 识别具有潜在抑制SARS-CoV-2主蛋白酶（Mpro）活性的天然生物活性化合物。
• 利用计算方法评估这些化合物与病毒蛋白酶的结合亲和力和相互作用稳定性。
• 基于结合能和结构相容性，从 *Anthocephalus cadamba* 中优先筛选出具有前景的先导化合物，以推进药物开发。
• 提出天然化合物或其类似物作为成本效益高、低毒性的COVID-19治疗候选药物。

提出的方法

• 采用B3LYP/631+G(d,p)水平的密度泛函理论（DFT）对来自 *Anthocephalus cadamba* 的九种生物活性天然化合物的基态几何构型进行建模。
• 进行分子对接模拟，以预测化合物与SARS-CoV-2主蛋白酶（Mpro）之间的结合亲和力。
• 在S-蛋白结合位点分析结合相互作用，以评估配体-蛋白复合物的特异性和稳定性。
• 计算并排序结合亲和力值（单位：kcal/mol），以识别最强效的抑制剂。
• 对优选化合物进行结构分析，包括氢键、疏水相互作用以及结合位点互补性的评估。
• 研究聚焦于天然存在的化合物，以优先筛选出合成成本低且副作用最小的候选药物。

实验结果

研究问题

• RQ1 来自 *Anthocephalus cadamba* 的哪些天然化合物对SARS-CoV-2主蛋白酶（Mpro）表现出最强的结合亲和力？
• RQ2 这些化合物的结构特征如何影响其与蛋白酶活性位点的相互作用？
• RQ3 计算方法能否可靠地从植物源生物活性化合物库中预测SARS-CoV-2 Mpro的潜在抑制剂？
• RQ4 在九种测试化合物中，结合亲和力的相对排序如何？
• RQ5 所识别的任何化合物是否表现出有利的结合模式，提示其在蛋白酶活性位点具有高特异性和稳定性？

主要发现

• 齐墩果酸在九种测试化合物中表现出最高的结合亲和力（最低结合能），表明其为最有效的SARS-CoV-2主蛋白酶预测抑制剂。
• 熊果酸在结合亲和力中排名第二，显示出作为抗COVID-19药物开发先导化合物的强劲潜力。
• 异戊基-异缬草酰胺、缬草酰胺、卡丹宾、异烟酰胺-氧化物、二氢氨基-卡丹宾、绿原酸戊酯以及D-肌醇根据结合能和相互作用特征，被确定为中等至有前景的抑制剂。
• 优选化合物在蛋白酶S-蛋白结合位点内表现出有利的氢键和疏水相互作用。
• 本研究突显了具有低成本合成和最小副作用的天然化合物作为抗SARS-CoV-2治疗药物的潜在可行性。
• 作者强调，需对这些化合物或其结构类似物进行体内验证，以确认其抗病毒疗效。