<i>In-silico</i> screening and identification of potential drug-like compounds for dengue-associated thrombocytopenia from <i>Carica papaya</i> leaf extracts

Dengue virus is a mosquito-borne pathogen that causes a variety of illnesses ranging from mild fever to severe and fatal dengue haemorrhagic fever or dengue shock syndrome. One of the major clinical manifestations of severe dengue infection is thrombocytopenia. The dengue non-structural protein 1 (NS1) is the primary protein that stimulates immune cells via toll-like receptor 4 (TLR4), induces platelets, and promotes aggregation, which could result in thrombocytopenia. The leaf extracts of <i>Carica papaya</i> seem to have therapeutic benefits in managing thrombocytopenia associated with dengue. The present study focuses on understanding the underlying mechanism of the use of papaya leaf extracts in treating thrombocytopenia. We have identified 124 phytocompounds that are present in the papaya leaf extract. The pharmacokinetics, molecular docking, binding free energy calculations, and molecular dynamic simulations were performed to investigate the drug-like properties, binding affinities, and interaction of phytocompounds with NS1 protein as well as the interactions of NS1 with TLR4. Three phytocompounds were found to bind with the ASN130, a crucial amino acid residue in the active site of the NS1 protein. Thus, we conclude that Rutin, Myricetin 3-rhamnoside, or Kaempferol 3-(2''-rhamnosylrutinoside) may serve as promising molecules by ameliorating thrombocytopenia in dengue-infected patients by interfering the interaction of NS1 with TLR4. These molecules can serve as drugs in the management of dengue-associated thrombocytopenia after verifying their effectiveness and assessing the drug potency, through additional in-vitro assays. Communicated by Ramaswamy H. Sarma登革病毒（Dengue virus）是一种经蚊虫传播的病原体，可引发多种疾病，临床表现从轻症发热，直至重症致死性登革出血热或登革休克综合征。重症登革感染的主要临床表现之一为血小板减少症（thrombocytopenia）。登革病毒非结构蛋白1（NS1，non-structural protein 1）是通过Toll样受体4（TLR4，toll-like receptor 4）刺激免疫细胞、诱导血小板并促进聚集的关键蛋白，该过程可引发血小板减少症。番木瓜（Carica papaya）叶提取物在治疗登革相关血小板减少症方面具有治疗益处。本研究旨在阐明番木瓜叶提取物治疗血小板减少症的潜在机制。我们已从番木瓜叶提取物中鉴定出124种植物化合物。通过药代动力学分析、分子对接、结合自由能计算及分子动力学模拟，本研究探究了这些植物化合物的类药特性、与NS1蛋白的结合亲和力及相互作用，同时考察了NS1与TLR4的相互作用。研究发现，有3种植物化合物可与NS1蛋白活性位点的关键氨基酸残基ASN130结合。据此，本研究得出结论：芦丁（Rutin）、杨梅素3-鼠李糖苷（Myricetin 3-rhamnoside）以及山奈酚3-(2''-鼠李糖基鼠李糖苷)（Kaempferol 3-(2''-rhamnosylrutinoside)）可通过干扰NS1与TLR4的相互作用，改善登革感染患者的血小板减少症，有望成为极具潜力的治疗分子。上述化合物需通过额外的体外实验验证其有效性并评估药物效价后，方可用于登革相关血小板减少症的临床管理。本文由拉马萨米·H·萨尔马（Ramaswamy H. Sarma）提交。