由SARS-CoV-2病毒引起的COVID-19大流行极大地影响了全球健康。新出现的证据表明,阿尔茨海默病(AD)之间存在复杂的相互作用,糖尿病(DM),和COVID-19。鉴于COVID-19参与其他疾病风险增加,迫切需要确定新的目标和药物来应对这些相互关联的健康挑战。溶血磷脂酸受体(LPAR),属于G蛋白偶联受体家族,与各种病理状况有关,包括炎症。在这方面,本研究旨在调查LPAR(特别是LPAR1,3,6)在AD,DM,和COVID-19通过网络分析,以及探索选定的抗AD的治疗潜力,抗DM药物如LPAR,SPIKE拮抗剂。我们使用Coremine医学数据库来识别与DM相关的基因,AD,和COVID-19。此外,STRING分析用于鉴定LPAR1、LPAR3和LPAR6的相互作用伴侣。此外,文献检索显示,市场上或临床研究中有78种药物用于治疗AD或DM.我们对这些药物与LPAR1、LPAR3和LPAR6进行了对接分析。此外,我们将LPAR1,LPAR3和LPAR6与COVID-19刺突蛋白复合物进行建模,并对选定药物与LPAR-刺突复合物进行对接研究.分析揭示了177个与AD有关的常见基因,DM,和COVID-19。蛋白质对接分析表明,LPAR(1,3&6)与病毒SPIKE蛋白有效结合,建议将它们作为病毒感染的目标。此外,抗AD和抗DM药物对LPAR的对接分析,SPIKE蛋白,LPAR-SPIKE复合体揭示了有希望的候选人,包括Lupron,奈拉马莫德,和尼洛替尼,说明药物再利用在药物发现过程中的重要性。这些药物表现出结合和抑制LPAR受体活性和SPIKE蛋白并干扰LPAR-SPIKE蛋白相互作用的能力。通过结合网络和基于目标的治疗干预方法,这项研究已经确定了几种药物,由于它们预期会干扰LPAR(1,3和6)和刺突蛋白复合物,因此可以重新用于治疗COVID-19.此外,还可以假设,在COVID-19感染期间联合使用这些已确定的药物可能不仅有助于减轻病毒的影响,而且可能有助于预防或管理与AD和DM相关的COVID后并发症.
The COVID-19 pandemic caused by the SARS-CoV-2 virus has greatly affected global health. Emerging evidence suggests a complex interplay between Alzheimer\'s disease (AD), diabetes (DM), and COVID-19. Given COVID-19\'s involvement in the increased risk of other diseases, there is an urgent need to identify novel targets and drugs to combat these interconnected health challenges. Lysophosphatidic acid receptors (LPARs), belonging to the G protein-coupled receptor family, have been implicated in various pathological conditions, including inflammation. In this regard, the study aimed to investigate the involvement of LPARs (specifically LPAR1, 3, 6) in the tri-directional relationship between AD, DM, and COVID-19 through network analysis, as well as explore the therapeutic potential of selected anti-AD, anti-DM drugs as LPAR, SPIKE antagonists. We used the Coremine Medical database to identify genes related to DM, AD, and COVID-19. Furthermore, STRING analysis was used to identify the interacting partners of LPAR1, LPAR3, and LPAR6. Additionally, a literature search revealed 78 drugs on the market or in clinical studies that were used for treating either AD or DM. We carried out docking analysis of these drugs against the LPAR1, LPAR3, and LPAR6. Furthermore, we modeled the LPAR1, LPAR3, and LPAR6 in a complex with the COVID-19 spike protein and performed a docking study of selected drugs with the LPAR-Spike complex. The analysis revealed 177 common genes implicated in AD, DM, and COVID-19. Protein-protein docking analysis demonstrated that LPAR (1,3 & 6) efficiently binds with the viral SPIKE protein, suggesting them as targets for viral infection. Furthermore, docking analysis of the anti-AD and anti-DM drugs against LPARs, SPIKE protein, and the LPARs-SPIKE complex revealed promising candidates, including lupron, neflamapimod, and nilotinib, stating the importance of drug repurposing in the drug discovery process. These drugs exhibited the ability to bind and inhibit the LPAR receptor activity and the SPIKE protein and interfere with LPAR-SPIKE protein interaction. Through a combined network and targeted-based therapeutic intervention approach, this study has identified several drugs that could be repurposed for treating COVID-19 due to their expected interference with LPAR(1, 3, and 6) and spike protein complexes. In addition, it can also be hypothesized that the co-administration of these identified drugs during COVID-19 infection may not only help mitigate the impact of the virus but also potentially contribute to the prevention or management of post-COVID complications related to AD and DM.