Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa.
Molecules. 2022 Jul 15;27(14):4515. doi: 10.3390/molecules27144515.
Influenza virus infections continue to be a significant and recurrent public health problem. Although vaccine efficacy varies, regular immunisation is the most effective method for suppressing the influenza virus. Antiviral drugs are available for influenza, although two of the four FDA-approved antiviral treatments have resulted in significant drug resistance. Therefore, new treatments are being sought to reduce the burden of flu-related illness. The time-consuming development of treatments for new and re-emerging diseases such as influenza and the high failure rate are increasing concerns. In this context, we used an in silico-based drug repurposing method to repurpose FDA-approved drugs as potential therapies against the H7N9 virus. To find potential inhibitors, a total of 2568 drugs were screened. Promacta, tucatinib, and lurasidone were identified as promising hits in the DrugBank database. According to the calculations of MM-GBSA, tucatinib (-54.11 kcal/mol) and Promacta (-56.20 kcal/mol) occupied the active site of neuraminidase with a higher binding affinity than the standard drug peramivir (-49.09 kcal/mol). Molecular dynamics (MD) simulation studies showed that the C-α atom backbones of the complexes of tucatinib and Promacta neuraminidase were stable throughout the simulation period. According to ADME analysis, the hit compounds have a high gastrointestinal absorption (GI) and do not exhibit properties that allow them to cross the blood-brain barrier (BBB). According to the in silico toxicity prediction, Promacta is not cardiotoxic, while lurasidone and tucatinib show only weak inhibition. Therefore, we propose to test these compounds experimentally against the influenza H7N9 virus. The investigation and validation of these potential H7N9 inhibitors would be beneficial in order to bring these compounds into clinical settings.
流感病毒感染仍然是一个重大且反复出现的公共卫生问题。尽管疫苗的效果各不相同，但定期免疫接种是抑制流感病毒最有效的方法。目前已有针对流感的抗病毒药物，但四种获得 FDA 批准的抗病毒治疗方法中有两种导致了显著的耐药性。因此，正在寻找新的治疗方法来减轻流感相关疾病的负担。新出现的流感等疾病的治疗方法的开发耗时较长，且失败率较高，这引起了人们的关注。在这种情况下，我们使用基于计算机的药物再利用方法，将 FDA 批准的药物重新用作针对 H7N9 病毒的潜在治疗方法。为了寻找潜在的抑制剂，共筛选了 2568 种药物。在 DrugBank 数据库中，Promacta、tucatinib 和 lurasidone 被确定为有希望的命中药物。根据 MM-GBSA 的计算，tucatinib（-54.11 kcal/mol）和 Promacta（-56.20 kcal/mol）与标准药物帕拉米韦（-49.09 kcal/mol）相比，占据了神经氨酸酶的活性位点，具有更高的结合亲和力。分子动力学（MD）模拟研究表明，tucatinib 和 Promacta 神经氨酸酶复合物的 C-α 原子骨架在整个模拟过程中都很稳定。根据 ADME 分析，这些命中化合物具有较高的胃肠道吸收率（GI），并且不具有穿透血脑屏障（BBB）的特性。根据计算机毒性预测，Promacta 没有心脏毒性，而 lurasidone 和 tucatinib 仅表现出较弱的抑制作用。因此，我们建议对这些化合物进行抗流感 H7N9 病毒的实验测试。研究和验证这些潜在的 H7N9 抑制剂将有助于将这些化合物应用于临床。
