针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）主要蛋白酶、刺突受体结合域和木瓜样蛋白酶受体的抗病毒药物苦瓜醇的计算机模拟分析

In silico analysis of balsaminol as anti-viral agents targeting SARS-CoV-2 main protease, spike receptor binding domain and papain-like protease receptors.

作者信息

Gaiya Daniel Danladi, Muhammad Aliyu, Musa Joy Sim, Auta Richard, Dadah Anthony John, Bello Rachael Oluwafunmilayo, Hassan Madinat, Eke Samuel Sunday, Odihi Rebecca Imoo, Sankey Musa

机构信息

Biology Unit, Air Force Institute of Technology, Nigerian Air Force Base, P.M.B 2104, Kaduna, Nigeria.

Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, P.M.B. 1045, Samaru Zaria, Nigeria.

出版信息

In Silico Pharmacol. 2024 Aug 16;12(2):75. doi: 10.1007/s40203-024-00241-0. eCollection 2024.

DOI:10.1007/s40203-024-00241-0

PMID:39155972

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11329488/

Abstract

UNLABELLED

Plant-derived phytochemicals from medicinal plants are becoming increasingly attractive natural sources of antimicrobial and antiviral agents due to their therapeutic value, mechanism of action, level of toxicity and bioavailability. The continued emergence of more immune-evasive strains and the rate of resistance to current antiviral drugs have created a need to identify new antiviral agents against SARS-CoV-2. This study investigated the antiviral potential of balsaminol, a bioactive compound from , and its inhibitory activities against SARS-CoV-2 receptor proteins. In this study, three Food and Drug Administration (FDA) COVID-19 approved drugs namely; nirmatrelvir, ritonavir and remdesivir were used as positive control. Molecular docking was performed to determine the predominant binding mode (most negative Gibbs free energy of binding/ΔG) and inhibitory activity of balsaminol against SARS-CoV-2 receptor proteins. The pharmacokinetics, toxicity, physicochemical and drug-like properties of balsaminol were evaluated to determine its potential as an active oral drug candidate as well as its non-toxicity in humans. The results show that balsaminol E has the highest binding affinity to the SARS CoV-2 papain-like protease (7CMD) with a free binding energy of - 8.7 kcal/mol, followed by balsaminol A interacting with the spike receptor binding domain (6VW1) with - 8.5 kcal/mol and balsaminol C had a binding energy of - 8.1 kcal/mol with the main protease (6LU7) comparable to the standard drugs namely ritonavir, nirmatrelvir and remdesivir. However, the ADMET and drug-like profile of balsaminol F favours it as a better potential drug candidate and inhibitor of the docked SARS-CoV-2 receptor proteins. Further preclinical studies are therefore recommended.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1007/s40203-024-00241-0.

摘要

未标记

来自药用植物的植物源植物化学物质因其治疗价值、作用机制、毒性水平和生物利用度，正日益成为抗菌和抗病毒药物具有吸引力的天然来源。越来越多具有免疫逃逸能力的毒株不断出现，以及对当前抗病毒药物的耐药率，使得有必要鉴定针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的新型抗病毒药物。本研究调查了来自[具体植物]的生物活性化合物苦瓜醇的抗病毒潜力及其对SARS-CoV-2受体蛋白的抑制活性。在本研究中，三种美国食品药品监督管理局（FDA）批准用于治疗2019冠状病毒病（COVID-19）的药物，即奈玛特韦、利托那韦和瑞德西韦用作阳性对照。进行分子对接以确定苦瓜醇对SARS-CoV-2受体蛋白的主要结合模式（结合的吉布斯自由能最负/ΔG）和抑制活性。评估了苦瓜醇的药代动力学、毒性、物理化学和类药性质，以确定其作为活性口服药物候选物的潜力以及在人体中的无毒性。结果表明，苦瓜醇E对SARS-CoV-2木瓜样蛋白酶（7CMD）具有最高的结合亲和力，自由结合能为-8.7千卡/摩尔，其次是苦瓜醇A与刺突受体结合域（6VW1）相互作用，结合能为-8.5千卡/摩尔，苦瓜醇C与主要蛋白酶（6LU7）的结合能为-8.1千卡/摩尔，与标准药物利托那韦、奈玛特韦和瑞德西韦相当。然而，苦瓜醇F的ADMET和类药特性使其更有潜力成为对接的SARS-CoV-2受体蛋白的药物候选物和抑制剂。因此，建议进行进一步的临床前研究。