Reappraisal of FDA approved drugs against Alzheimer’s disease based on differential gene expression and protein interaction network analysis: an in silico approach

Alzheimer’s disease (AD), a most prevailing neurodegenerative disorder with turbulence in cognitive and behavioural abilities, epitomizes one of the highest unmet medical requirements. The current AD treatment focuses merely on symptomatic relief, this explains a dearth in drug research oriented towards unwinding of disease specific druggable targets. On the other hand, toxicity and poor bioavailability hamper the evolution of novel chemical entities (NCE) in clinical trials. Drug repurposing offers a gateway to rejuvenate new therapeutic applications for existing approved drugs. This study concentrates on the identification of potential druggable AD targets and screening of FDA approved drugs with a concept of drug repurposing. differentially expressed genes (DEGs) were identified in frontal cortex, temporal cortex and hippocampus in AD patients from Gene Expression Omnibus (GEO) dataset GSE36980. Protein-protein interaction (PPI) analysis revealed SERPINA3 and BDNF to possess high node degree interaction with literature derived candidate genes (LDGs) in AD males and females, respectively, thus were selected as potential AD targets. Subsequently, FDA approved drugs were screened through the above shortlisted targets and were ranked based on molecular docking and MM-GBSA energy calculations using Glide and Prime tools, respectively. Drugs possessing best docking score and maximum binding energy were further evaluated through molecular dynamics simulation studies, which revealed the affinity of Tiludronic acid and Olsalazine towards SERPINA3 and BDNF, respectively. Communicated by Ramaswamy H. Sarma

阿尔茨海默病（Alzheimer’s Disease, AD）是一种最为常见的神经退行性疾病，会引发认知与行为能力紊乱，是未被满足医疗需求程度最高的病症之一。当前阿尔茨海默病的治疗仅能实现症状缓解，这也造成针对疾病特异性可药用靶点的药物研发严重匮乏。此外，毒性与较差的生物利用度阻碍了新型化学实体（Novel Chemical Entities, NCE）在临床试验中的研发进程。药物重定位为已获批药物开发全新治疗用途提供了可行路径。本研究聚焦于潜在阿尔茨海默病可药用靶点的识别，并基于药物重定位理念筛选FDA获批药物。研究从基因表达综合数据库（Gene Expression Omnibus, GEO）的GSE36980数据集获取阿尔茨海默病患者的额叶皮层、颞叶皮层与海马体样本，从中鉴定得到差异表达基因（Differentially Expressed Genes, DEGs）。蛋白质-蛋白质相互作用（Protein-Protein Interaction, PPI）分析结果显示，SERPINA3与BDNF分别在阿尔茨海默病男性与女性患者中，与文献来源候选基因（Literature Derived Candidate Genes, LDGs）存在较高的节点度相互作用，因此被选为潜在阿尔茨海默病治疗靶点。随后，基于上述筛选得到的靶点对FDA获批药物进行筛选，并分别通过Glide工具与Prime工具开展分子对接与MM-GBSA能量计算，对药物进行优先级排序。选取对接评分最优、结合能最高的药物开展分子动力学模拟研究，结果显示替鲁膦酸（Tiludronic acid）与奥沙拉嗪（Olsalazine）分别对SERPINA3与BDNF具有较高结合亲和力。本文由Ramaswamy H. Sarma 供稿。