Kumar Anuj, Sharma Mansi, Richardson Christopher D, Kelvin David J
Laboratory of Immunity, Shantou University Medical College, Shantou, China.
Department of Microbiology and Immunology, Canadian Centre for Vaccinology CCfV, Faculty of Medicine, Dalhousie University, Halifax, Canada.
Front Mol Biosci. 2022 May 10;9:898874. doi: 10.3389/fmolb.2022.898874. eCollection 2022.
The ongoing pandemic coronavirus disease (COVID-19) caused by a novel corona virus, namely, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has had a major impact on global public health. COVID-19 cases continue to increase across the globe with high mortality rates in immunocompromised patients. There is still a pressing demand for drug discovery and vaccine development against this highly contagious disease. To design and develop antiviral drugs against COVID-19, the main protease (M) has emerged as one of the important drug targets. In this context, the present work explored Jadwar ()-derived natural alkaloids as potential inhibitors against M of SARS-CoV-2 by employing a combination of molecular docking and molecular dynamic simulation-based methods. Molecular docking and interaction profile analysis revealed strong binding on the M functional domain with four natural alkaloids . panicutine (-7.4 kcal/mol), vilmorrianone (-7.0 kcal/mol), denudatine (-6.0 kcal/mol), and condelphine (-5.9 kcal/mol). The molecular docking results evaluated by using the MD simulations on 200 nanoseconds confirmed highly stable interactions of these compounds with the M. Additionally, mechanics/generalized Born/Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations also affirmed the docking results. Natural alkaloids explored in the present study possess the essential drug-likeness properties, namely, absorption, distribution, metabolism, and excretion (ADME), and are in accordance with Lipinski's rule of five. The results of this study suggest that these four bioactive molecules, namely, condelphine, denudatine, panicutine, and vilmorrianone, might be effective candidates against COVID-19 and can be further investigated using a number of experimental methods.
由新型冠状病毒，即严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的持续性大流行性冠状病毒病（COVID-19），对全球公共卫生产生了重大影响。COVID-19病例在全球范围内持续增加，免疫功能低下患者的死亡率很高。针对这种高传染性疾病的药物研发和疫苗开发仍然有迫切需求。为了设计和开发针对COVID-19的抗病毒药物，主要蛋白酶（M）已成为重要的药物靶点之一。在此背景下，本研究通过结合分子对接和基于分子动力学模拟的方法，探索了来自Jadwar的天然生物碱作为针对SARS-CoV-2的M的潜在抑制剂。分子对接和相互作用谱分析显示，四种天然生物碱，即panicutine（-7.4千卡/摩尔）、vilmorrianone（-7.0千卡/摩尔）、去甲乌药碱（-6.0千卡/摩尔）和coniine（-5.9千卡/摩尔）与M功能域有强结合。通过200纳秒的分子动力学模拟评估的分子对接结果证实了这些化合物与M的高度稳定相互作用。此外，力学/广义玻恩/泊松-玻尔兹曼表面积（MM/G/P/BSA）自由能计算也证实了对接结果。本研究中探索的天然生物碱具有基本的类药物性质，即吸收、分布、代谢和排泄（ADME），并且符合Lipinski的五规则。本研究结果表明，这四种生物活性分子，即coniine、去甲乌药碱、panicutine和vilmorrianone，可能是对抗COVID-19的有效候选物，可以使用多种实验方法进一步研究。
