The emergence of zoonotic monkeypox (MPX) disease, caused by the double-stranded DNA monkeypox virus (MPXV), has become a global threat. Due to unavailability of a specific small molecule drug for MPX, this study investigated Moringa oleifera phytochemicals to find potent and safe inhibitors of DNA Polymerase (DNA Pol), a poxvirus drug target due to its role in the viral life cycle. For that, 146 phytochemicals were screened through drug-likeness and molecular docking analyses. Among these, 136 compounds exhibited drug-like properties, with Gossypetin showing the highest binding affinity (− 7.8 kcal/mol), followed by Riboflavin (− 7.6 kcal/mol) and Ellagic acid (− 7.6 kcal/mol). In comparison, the control drugs Cidofovir and Brincidofovir displayed lower binding affinities, with binding energies of − 6.0 kcal/mol and − 5.1 kcal/mol, respectively. Hydrogen bonds, electrostatic and hydrophobic interactions were the main non-bond interactions between inhibitors and protein active site. The identified compounds were further evaluated using molecular dynamics simulation, density functional theory analysis and ADMET analysis. Molecular dynamics simulations conducted over 200 ns revealed that DNA Pol-Gossypetin complex was not stable, however, Riboflavin and Ellagic acid complexes showed excellent stability indicating them as better DNA Pol inhibitors. The density functional theory analysis exhibited the chemical reactivity of these inhibitor compounds. The ADMET analysis suggested that the top phytochemicals were safe and showed no toxicity. In conclusion, this study has identified Riboflavin and Ellagic acid as potential DNA Pol inhibitors to control MPXV. Further experimental assays and clinical trials are needed to confirm their activity against the disease.

Graphical Abstract

中文翻译：

---

利用辣木植物化学物质抑制猴痘病毒 DNA 聚合酶：药物相似性、分子对接、分子动力学模拟和密度泛函理论的计算研究

由双链DNA猴痘病毒（MPXV）引起的人畜共患猴痘（MPX）疾病的出现已成为全球威胁。由于缺乏针对 MPX 的特定小分子药物，本研究研究了辣木植物化学物质，以寻找有效且安全的 DNA 聚合酶 (DNA Pol) 抑制剂，DNA 聚合酶是痘病毒药物靶标，因为它在病毒生命周期中发挥作用。为此，通过药物相似性和分子对接分析筛选了 146 种植物化学物质。其中，136种化合物表现出类似药物的特性，其中棉素显示出最高的结合亲和力（− 7.8 kcal/mol），其次是核黄素（− 7.6 kcal/mol）和鞣花酸（− 7.6 kcal/mol）。相比之下，对照药物西多福韦和布林西多福韦表现出较低的结合亲和力，结合能分别为−6.0 kcal/mol和−5.1 kcal/mol。氢键、静电和疏水相互作用是抑制剂与蛋白质活性位点之间的主要非键相互作用。使用分子动力学模拟、密度泛函理论分析和 ADMET 分析对鉴定出的化合物进行了进一步评估。超过 200 ns 进行的分子动力学模拟表明，DNA Pol-Gossypetin 复合物不稳定，然而，核黄素和鞣花酸复合物表现出优异的稳定性，表明它们是更好的 DNA Pol 抑制剂。密度泛函理论分析显示了这些抑制剂化合物的化学反应活性。 ADMET 分析表明，顶级植物化学物质是安全的，没有毒性。总之，本研究已确定核黄素和鞣花酸作为潜在的 DNA Pol 抑制剂来控制 MPXV。需要进一步的实验测定和临床试验来确认它们对疾病的活性。

图形概要