Genomics-driven drug repurposing and novel targets identification for sickle cell disease in Saudi patients.

Abstract

Sickle cell disease (SCD) is an inherited blood disorder characterized by chronic hemolysis, inflammation, and vaso-occlusive crises (VOC), leading to multiple complications and reduced life expectancy in affected individuals. Limited effective treatment options are currently available; however, recent genomic findings from underrepresented populations (Saudi Arabians) have offered new hope for predicting molecularly guided treatments. This study aimed to identify approved drugs suitable for repurposing based on their interactions with SCD-associated genetic variants and to discover novel druggable targets within genetic pathways linked to disease severity by utilizing genome-wide association study (GWAS) data from Saudi SCD patients. Bioinformatic pipelines were used to evaluate drug-gene interactions and identify potential therapeutic targets based on GWAS data derived from the Saudi population. Approved drugs were suggested for repurposing according to their interactions with genes known to impact SCD pathophysiology, using the Drug-Gene Interaction Database (DGIdb 5.0). New drug targets were also proposed by assessing the simulated binding pockets of gene products, using 3D protein structures from the Protein Data Bank (PDB) and the AlphaFold database. Molecules with higher druggability scores, as estimated by the DoGSiteScorer database, were predicted to have a higher success rate for new SCD treatment development. Our analysis identified 78 approved medications with potential for repurposing in SCD; this list was narrowed to 21 candidates based on safety profiles and interactions with key genetic pathways. Among these, simvastatin, allopurinol, omalizumab, canakinumab, and etanercept were suggested as the most promising agents. Furthermore, novel drug targets encoded by olfactory receptor (OR) gene clusters (OR51V1, OR52A1, OR52A5, OR51B5, and OR51S1), TRIM genes, SIDT2, and CADM3 displayed high druggability scores. This study provides a robust framework for drug repurposing and novel drug discovery in SCD, particularly tailored to the Saudi population. The findings underscore the potential of leveraging genomic data to identify targeted therapies, offering a pathway to more personalized and effective treatments for SCD patients. Future clinical trials are essential to validate these findings and translate them into clinical practice.