Drug Repurposing for Amyotrophic Lateral Sclerosis Based on Gene Expression Similarity and Structural Similarity: A Cheminformatics, Genomic and Network-Based Analysis

Background: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurological disorder with increasing prevalence rates. Currently, only 8 FDA-approved drugs and 44 clinical trials exist for ALS treatment specifying the lacuna in disease-specific treatment. Drug repurposing, an alternative approach, is gaining huge importance. This study aims to identify potential repurposable compounds using gene expression analysis and structural similarity approaches. Methods: GSE833 and GSE3307 were analysed to retrieve Differentially Expressed Genes (DEGs) which were utilized to identify compounds reversing the gene signatures from LINCS. SMILES of ALS-specific FDA-approved and clinical trial compounds were used to retrieve structurally similar drugs from DrugBank. Drug-Target-Network (DTN) was constructed for the identified compounds to retrieve drug targets which were further subjected to functional enrichment analysis. Results: GSE833 retrieved 13 & 5 whereas GSE3307 retrieved 280 & 430 significant upregulated and downregulated DEGs respectively. Gene expression similarity identified 213 approved drugs. Structural similarity analysis of 44 compounds resulted in 411 approved and investigational compounds. DTN was constructed for 266 compounds to identify drug targets. Functional enrichment analysis resulted in neuroinflammatory response, cAMP signaling, PI3K-AKT signaling, and oxidative stress pathways. A preliminary relevancy check identified previous association of 105 compounds in ALS research, validating the approach, with 172 potential repurposable compounds.