Hashim Hayder O, Al-Shuhaib Jafar M B, Mohammed Mudher K, Al-Shuhaib Mohammed Baqur S
Department of Clinical Laboratory Sciences, College of Pharmacy, University of Babylon, Babil, 51001, Iraq.
College of Medicine, University of Warith Al-Anbiyaa, Karbala, 56001, Iraq.
Mol Biotechnol. 2024 Aug 3. doi: 10.1007/s12033-024-01246-y.
Monkeypox is an infectious disease resulting from the monkeypox virus, and its fatality rate varies depending on the virus clade and the location of the outbreak. In monkeypox virus, methyltransferase (MTase) plays a crucial role in modifying the cap structure of viral mRNA. This alteration assists the virus in evading the host's immune system, enhances viral protein synthesis, and ultimately enables successful infection and replication within host cells. Given the significance of MTase in viral infection and spread within the host, our study aimed to identify a natural inhibitor for this enzyme using docking and molecular dynamic (MD) simulations. We collected a total of 12,971 natural compounds from 200 medicinal plants in the Middle East. After eliminating duplicate compounds, we had 5,749 unique ligand conformers, which we then subjected to high-throughput virtual screening against MTase. The most promising hits were further evaluated using the extra-precision (XP) tool. The affinity of these hits was also assessed by Prime-Molecular Mechanics/Generalized Born Surface Area (MMGBSA) tool. The analysis revealed that two standard controls (sinefungin and TO1119) and two Middle-Eastern compounds (folic acid and 1,2,4,6-tetragalloylglucose) exhibited the best XP docking scores. According to Prime MMGBSA calculations, the Middle-Eastern compounds showed higher affinities, with values of - 60.61 kcal/mol for 1,2,4,6-tetragalloylglucose and - 51.87 kcal/mol for folic acid, surpassing the controls (TO1119 at - 35.71 kcal/mol and sinefungin at - 31.51 kcal/mol). In the majority of Molecular dynamic (MD) simulations, folic acid exhibited demonstrated greater stability than sinefungin. Further investigation revealed that folic acid occupied a critical position in the active site of MTase, which reduced its interaction with the mRNA substrate. Based on these findings, it can be concluded that folic acid is a highly promising natural compound for potential use in the cost-effective treatment of monkeypox virus. The identification of folic acid as a potential antiviral agent highlights the importance of nature in providing new therapeutic uses that have significant implications for global health, particularly in regions where monkeypox viral outbreaks are prevalent. However, it is essential to note that further wet-lab validations are necessary to confirm its efficacy for treatment in a medical context.
猴痘是由猴痘病毒引起的一种传染病，其致死率因病毒分支和疫情发生地点而异。在猴痘病毒中，甲基转移酶（MTase）在修饰病毒mRNA的帽结构方面发挥着关键作用。这种改变有助于病毒逃避免疫系统，增强病毒蛋白合成，并最终使其能够在宿主细胞内成功感染和复制。鉴于MTase在病毒感染和在宿主体内传播中的重要性，我们的研究旨在通过对接和分子动力学（MD）模拟来确定该酶的一种天然抑制剂。我们从中东地区的200种药用植物中总共收集了12971种天然化合物。在去除重复化合物后，我们得到了5749种独特的配体构象，然后对其进行针对MTase的高通量虚拟筛选。最有前景的命中化合物使用超精确（XP）工具进行进一步评估。这些命中化合物的亲和力也通过Prime-分子力学/广义玻恩表面积（MMGBSA）工具进行评估。分析表明，两种标准对照（辛芬净和TO1119）以及两种中东化合物（叶酸和1,2,4,6-四没食子酰葡萄糖）表现出最佳的XP对接分数。根据Prime MMGBSA计算，中东化合物显示出更高的亲和力，1,2,4,6-四没食子酰葡萄糖的值为-60.61千卡/摩尔，叶酸的值为-51.87千卡/摩尔，超过了对照（TO1119为-35.71千卡/摩尔，辛芬净为-31.51千卡/摩尔）。在大多数分子动力学（MD）模拟中，叶酸表现出比辛芬净更高的稳定性。进一步研究表明，叶酸在MTase的活性位点占据关键位置，这减少了它与mRNA底物的相互作用。基于这些发现，可以得出结论，叶酸是一种非常有前景的天然化合物，有可能用于猴痘病毒的经济有效治疗。叶酸作为一种潜在抗病毒剂的鉴定突出了自然界在提供对全球健康具有重大意义的新治疗用途方面的重要性，特别是在猴痘病毒疫情流行的地区。然而，必须注意的是，需要进一步的湿实验室验证来确认其在医学背景下的治疗效果。
