Bhattacharjee Arittra, Ahammad Ishtiaque, Chowdhury Zeshan Mahmud, Das Keshob Chandra, Keya Chaman Ara, Salimullah Md
Bioinformatics Division, National Institute of Biotechnology, Ganakbari, Ashulia, Savar, Dhaka, 1349, Bangladesh.
Molecular Biotechnology Division, National Institute of Biotechnology, Ganakbari, Ashulia, Savar, Dhaka, 1349, Bangladesh.
Mol Biotechnol. 2024 Apr;66(4):626-640. doi: 10.1007/s12033-022-00595-w. Epub 2022 Nov 10.
Monkeypox Virus (MPXV), the causative agent of Monkeypox (MPX) disease, is an emerging zoonotic pathogen spreading in different endemic and non-endemic nations and creating outbreaks. MPX treatment mainly includes Cidofovir and Tecovirimat but they have several side effects and solely depending on these drugs may promote the emergence of drug-resistant variants. Hence, new drugs are required to control the spread of the disease. In this study, we explored the MPXV proteome to suggest repurposable drugs. DrugBank screening revealed drugs such as Brinzolamide, Dorzolamide, Methazolamide, Zidovudine, Gemcitabine, Hydroxyurea, Fludarabine, and Tecovirimat as controls. Structural analogs of these compounds were extracted from ChEMBL Database. After Molecular docking and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET)-based screening, we identified Zidovudine (binding affinity-5.9 kcal/mol) and a Harmala alkaloid (2S,4R)-4-(9H-Pyrido[3,4-b]indol-1-yl)-1,2,4-butanetriol (binding affinity - 6.6 kcal/mol) against L2R receptor (Thymidine Kinase). Moreover, Fludarabine (binding affinity - 6.4 kcal/mol) and 5'-Dehydroadenosine (binding affinity - 6.4 kcal/mol) can strongly interact with the I4L receptor (Ribonucleotide reductase large subunit R1). Molecular Dynamics (MD) simulations suggest all of these compounds can change the C-alpha backbone, residue mobility, compactness, and solvent accessible surface area of L2R and I4L. Our results strongly suggest that these drug repurposing small molecules are worth exploring in vivo and in vitro for clinical applications.
猴痘病毒（MPXV）是猴痘（MPX）疾病的病原体，是一种正在出现的人畜共患病原体，在不同的地方流行和非流行国家传播并引发疫情。MPX的治疗主要包括西多福韦和替考韦瑞玛，但它们有几种副作用，仅依赖这些药物可能会促进耐药变体的出现。因此，需要新的药物来控制疾病的传播。在本研究中，我们探索了MPXV蛋白质组以提出可重新利用的药物。药物银行筛选显示了布林佐胺、多佐胺、甲醋唑胺、齐多夫定、吉西他滨、羟基脲、氟达拉滨等药物以及作为对照的替考韦瑞玛。这些化合物的结构类似物从ChEMBL数据库中提取。经过分子对接以及基于吸收、分布、代谢、排泄和毒性（ADMET）的筛选，我们确定了针对L2R受体（胸苷激酶）的齐多夫定（结合亲和力-5.9千卡/摩尔）和一种哈尔满生物碱（2S,4R）-4-（9H-吡啶并[3,4-b]吲哚-1-基）-1,2,4-丁三醇（结合亲和力-6.6千卡/摩尔）。此外，氟达拉滨（结合亲和力-6.4千卡/摩尔）和5'-脱氢腺苷（结合亲和力-6.4千卡/摩尔）可以与I4L受体（核糖核苷酸还原酶大亚基R1）强烈相互作用。分子动力学（MD）模拟表明，所有这些化合物都可以改变L2R和I4L的C-α主链、残基流动性、紧密性和溶剂可及表面积。我们的结果强烈表明，这些药物重新利用的小分子在体内和体外临床应用方面值得探索。
