Gene expression analysis reveals GRIN1, SYT1, and SYN2 as significant therapeutic targets and drug repurposing reveals lorazepam and lorediplon as potent inhibitors to manage Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a slowly progressive neurodegenerative disease and a leading cause of dementia. We aim to identify key genes for the development of therapeutic targets and biomarkers for potential treatments for AD. Meta-analysis was performed on six microarray datasets and identified the differentially expressed genes between healthy and Alzheimer’s disease samples. Thereafter, we filtered out the common genes which were present in at least four microarray datasets for downstream analysis. We have constructed a gene-gene network for the common genes and identified six hub genes. Furthermore, we investigated the regulatory mechanisms of these hub genes by analysing their interaction with miRNAs and transcription factors. The gene ontology analysis results highlighted the enriched terms significantly associated with hub genes. Through an extensive literature survey, we found that three of the hub genes including GRIN1, SYN2, and SYT1 were critically involved in disease development. To leverage existing drugs for potential repurposing, we predicted drug-gene interaction using the drug-gene interaction database, and performed molecular docking studies. The docking results revealed that the drug compounds had strong interactions and favorable binding with selected hub genes. Lorazepam exhibits a binding energy of −7.3 kcal/mol with GRIN1, Lorediplon exhibits binding energies of −7.7 kcal/mol and −6.3 kcal/mol with the SYT1, and SYN2 respectively. In addition, 100 ns molecular dynamics simulations were carried out for the top complexes and apo protein as well. Furthermore, the MM-PBSA free energy calculations also revealed that these complexes are stable and had favorable energies. According to our study, the identified hub gene could serve as a biomarker as well as a therapeutic target for AD, and the proposed repurposed drug molecules appear to have promising efficacy in treating the disease. Communicated by Ramaswamy H. Sarma