Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, PO Box 1334, Durban, 4000, South Africa.
Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, PO Box 1334, Durban, 4000, South Africa.
J Mol Graph Model. 2022 Jul;114:108185. doi: 10.1016/j.jmgm.2022.108185. Epub 2022 Apr 12.
The coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is highly pathogenic and transmissible. It is mediated by the binding of viral spike proteins to human cells via entry and replication processes involving human angiotensin converting enzyme-2 (hACE2), transmembrane serine protease (TMPRSS2) and cathepsin L (Cath L). The identification of novel therapeutics that can modulate viral entry or replication has been of research interest and would be germane in managing COVID-19 subjects. This study investigated the structure-activity relationship inhibitory potential of 99 phytocompounds from selected African botanicals with proven therapeutic benefits against respiratory diseases focusing on SARS-CoV-2's human cell proteins (hACE2, TMPRSS2, and Cathepsin L) as druggable targets using computational methods. Evaluation of the binding energies of the phytocompounds showed that two compounds, Abrusoside A (-63.393 kcal/mol) and Kaempferol-3-O-rutinoside (-58.939 kcal/mol) had stronger affinity for the exopeptidase site of hACE2 compared to the reference drug, MLN-4760 (-54.545 kcal/mol). The study further revealed that Verbascoside (-63.338 kcal/mol), Abrectorin (-37.880 kcal/mol), and Friedelin (-36.989 kcal/mol) are potential inhibitors of TMPRSS2 compared to Nafamostat (-36.186 kcal/mol), while Hemiphloin (-41.425 kcal/mol), Quercetin-3-O-rutinoside (-37.257 kcal/mol), and Myricetin-3-O-galactoside (-36.342 kcal/mol) are potential inhibitors of Cathepsin L relative to Bafilomycin A1 (-38.180 kcal/mol). The structural analysis suggests that these compounds do not compromise the structural integrity of the proteins, but rather stabilized and interacted well with the active site amino acid residues critical to inhibition of the respective proteins. Overall, the findings from this study are suggestive of the structural mechanism of inhibitory action of the identified leads against the proteins critical for SARS-CoV-2 to enter the human host cell. While the study has lent credence to the significant role the compounds could play in developing potent SARS-CoV-2 candidate drugs against COVID-19, further structural refinement, and modifications of the compounds for subsequent in vitro as well as preclinical and clinical evaluations are underway.
新型冠状病毒病 2019（COVID-19）是由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）引起的，其具有高度的致病性和传染性。它通过病毒刺突蛋白与人类细胞的结合来介导，该结合通过涉及人类血管紧张素转换酶-2（hACE2）、跨膜丝氨酸蛋白酶（TMPRSS2）和组织蛋白酶 L（Cath L）的进入和复制过程来实现。寻找能够调节病毒进入或复制的新型治疗药物一直是研究的热点，对于管理 COVID-19 患者具有重要意义。本研究使用计算方法，研究了来自选定具有治疗呼吸疾病功效的非洲植物的 99 种植物化合物的结构-活性关系抑制潜力，这些化合物针对的是 SARS-CoV-2 的人类细胞蛋白（hACE2、TMPRSS2 和 Cathepsin L）作为可成药靶点。对植物化合物结合能的评估表明，与参考药物 MLN-4760（-54.545 kcal/mol）相比，两种化合物，羽扇豆醇 A（-63.393 kcal/mol）和山奈酚-3-O-芸香糖苷（-58.939 kcal/mol）对 hACE2 的外肽酶位点具有更强的亲和力。该研究还表明，与 Nafamostat（-36.186 kcal/mol）相比，毛蕊花糖苷（-63.338 kcal/mol）、阿伯瑞丁（-37.880 kcal/mol）和friedelin（-36.989 kcal/mol）是 TMPRSS2 的潜在抑制剂，而半胱氨酸（-41.425 kcal/mol）、槲皮素-3-O-芸香糖苷（-37.257 kcal/mol）和杨梅素-3-O-半乳糖苷（-36.342 kcal/mol）是 Cathepsin L 的潜在抑制剂，相对于 Bafilomycin A1（-38.180 kcal/mol）。结构分析表明，这些化合物不会破坏蛋白质的结构完整性，而是稳定并与各自蛋白质的抑制相关的活性位点氨基酸残基很好地相互作用。总的来说，这项研究的结果表明，鉴定的先导化合物对 SARS-CoV-2 进入人类宿主细胞至关重要的蛋白质具有抑制作用的结构机制。虽然该研究表明这些化合物在开发针对 COVID-19 的新型 SARS-CoV-2 候选药物方面可能发挥重要作用，但目前正在对这些化合物进行进一步的结构优化和修饰，以进行随后的体外以及临床前和临床评估。
