Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan.
Department of Biochemistry, University of Agriculture Faisalabad, Faisalabad 38000, Pakistan.
Molecules. 2023 Mar 16;28(6):2675. doi: 10.3390/molecules28062675.
Hepatitis E virus (HEV) is the notable causative agent of acute and chronic hepatic, renal, pancreatic, neurological, and hematopoietic blood cell infections with high risk in immunocompromised patients. Hepatic failure is mostly documented among adults, pregnant women, and patients with preexisting liver disease. HEV is a positive sense RNA virus of 7.2 kb genome size with typically three open reading frames (ORFs) which play essential roles in viral replication, genome assembly, and transcription. The mutational substitution in the viral RNA genome makes more it difficult to understand the actual relationship in the host-virus association. ORFs of HEV encode different structural and non-structural proteins and one of them is the capsid protein which is coded by ORF2. The capsid protein mediates the encapsulation of the viral genome as well as being involved in virion assembly. In the current study, the ligand-based docking approach was employed to inhibit the active amino acids of the viral capsid protein. Depending upon S-score, ADMET profiling, and drug scanning, the top ten tetrapeptides were selected as potential drug candidates with no toxicity counter to HEV receptor protein. The S-score or docking score is a mathematical function which predicts the binding affinities of docked complexes. The binding affinity of the predicted drug-target complexes helps in the selectivity of the desired compound as a potential drug. The best two selected peptides (i.e., TDGH with S-score of -8.5 and EGDE with S-score of -8.0) interacted with the active site amino acids of the capsid protein (i.e., Arg399, Gln420, and Asp444). The molecular dynamics simulations of RMSD trajectories of TDGH-capsid protein and EDGE-capsid protein have revealed that both docked complexes were structurally stable. The study revealed that these tetrapeptides would serve as strong potential inhibitors and a starting point for the development of new drug molecules against the HEV capsid protein. In future, in vivo studies are needed to explore selected peptides as potential drug candidates.
戊型肝炎病毒 (HEV) 是导致急性和慢性肝、肾、胰腺、神经和造血血细胞感染的重要病原体，在免疫功能低下的患者中风险较高。肝衰竭主要发生在成年人、孕妇和患有原有肝脏疾病的患者中。HEV 是一种 7.2kb 基因组大小的正链 RNA 病毒，通常具有三个开放阅读框 (ORF)，这些 ORF 在病毒复制、基因组组装和转录中发挥重要作用。病毒 RNA 基因组中的突变取代使得更难理解宿主-病毒关联的实际关系。HEV 的 ORFs 编码不同的结构和非结构蛋白，其中之一是衣壳蛋白，由 ORF2 编码。衣壳蛋白介导病毒基因组的包装，并参与病毒粒子的组装。在目前的研究中，采用基于配体的对接方法来抑制病毒衣壳蛋白的活性氨基酸。根据 S 评分、ADMET 分析和药物扫描，选择了前 10 个四肽作为潜在的无毒性抗 HEV 受体蛋白药物候选物。S 评分或对接评分是一种数学函数，可预测对接复合物的结合亲和力。预测的药物-靶标复合物的结合亲和力有助于所需化合物作为潜在药物的选择性。选择的两个最佳肽 (即 S 评分为-8.5 的 TDGH 和 S 评分为-8.0 的 EGDE) 与衣壳蛋白的活性位点氨基酸 (即 Arg399、Gln420 和 Asp444) 相互作用。TDGH-衣壳蛋白和 EDGE-衣壳蛋白的 RMSD 轨迹分子动力学模拟表明，两个对接复合物结构都很稳定。研究表明，这些四肽将作为强有力的潜在抑制剂，并为开发针对 HEV 衣壳蛋白的新型药物分子提供起点。未来需要进行体内研究，以探索选定的肽作为潜在的药物候选物。
