Special Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz University, 21362, Jeddah, Saudi Arabia.
Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, 21362, Jeddah, Saudi Arabia.
Sci Rep. 2023 Sep 4;13(1):14570. doi: 10.1038/s41598-023-41820-z.
Monkeypox viral infection is an emerging threat and a major concern for the human population. The lack of drug molecules to treat this disease may worsen the problem. Identifying potential drug targets can significantly improve the process of developing potent drug molecules for treating monkeypox. The proteins responsible for viral replication are attractive drug targets. Identifying potential inhibitors from known drug molecules that target these proteins can be key to finding a cure for monkeypox. In this work, two viral proteins, DNA-dependent RNA polymerase (DdRp) and viral core cysteine proteinase, were considered as potential drug targets. Sixteen antibiotic drugs from the tetracycline class were screened against both viral proteins through high-throughput virtual screening. These tetracycline class of antibiotic drugs have the ability to inhibit bacterial protein synthesis, which makes these antibiotics drugs a prominent candidate for drug repurposing. Based on the screening result obtained against DdRp, top two compounds, namely Tigecycline and Eravacycline with docking scores of - 8.88 and - 7.87 kcal/mol, respectively, were selected for further analysis. Omadacycline and minocycline, with docking scores of - 10.60 and - 7.51 kcal/mol, are the top two compounds obtained after screening proteinase with the drug library. These compounds, along with reference compounds GTP for DdRp and tecovirimat for proteinase, were used to form protein-ligand complexes, followed by their evaluation through a 300 ns molecular dynamic simulation. The MM/GBSA binding free energy calculation and principal components analysis of these selected complexes were also conducted for understanding the dynamic stability and binding affinity of these compounds with respective target proteins. Overall, this study demonstrates the repurposing of tetracycline-derived drugs as a therapeutic solution for monkeypox viral infection.
猴痘病毒感染是一种新出现的威胁，也是人类关注的主要问题。缺乏治疗这种疾病的药物分子可能会使问题恶化。鉴定潜在的药物靶点可以显著改善开发治疗猴痘的有效药物分子的过程。负责病毒复制的蛋白质是有吸引力的药物靶点。从针对这些蛋白质的已知药物分子中鉴定潜在的抑制剂可能是找到治疗猴痘方法的关键。在这项工作中，考虑了两种病毒蛋白，即 DNA 依赖性 RNA 聚合酶（DdRp）和病毒核心半胱氨酸蛋白酶，作为潜在的药物靶点。通过高通量虚拟筛选，对这两种病毒蛋白进行了来自四环素类的 16 种抗生素药物的筛选。这些四环素类抗生素药物具有抑制细菌蛋白质合成的能力，这使得这些抗生素药物成为药物再利用的突出候选者。根据针对 DdRp 的筛选结果，选择了两种排名靠前的化合物，即替加环素（Tigecycline）和依拉环素（Eravacycline），它们的对接得分分别为-8.88 和-7.87 kcal/mol。经过用药物库筛选蛋白酶，得到了两种排名靠前的化合物，即奥马环素（Omadacycline）和米诺环素（Minocycline），它们的对接得分分别为-10.60 和-7.51 kcal/mol。这些化合物以及 DdRp 的参考化合物 GTP 和蛋白酶的参考化合物特考韦瑞（Tcovirimat）被用于形成蛋白-配体复合物，然后通过 300 ns 分子动力学模拟对其进行评估。还对这些选定的复合物进行了 MM/GBSA 结合自由能计算和主成分分析，以了解这些化合物与各自靶蛋白的动态稳定性和结合亲和力。总的来说，这项研究表明，四环素类衍生药物可作为治疗猴痘病毒感染的治疗方法。
