From Genomics to Therapy: Repurposing Approved Drugs and Identifying Novel Targets for Sickle Cell Disease in Saudi Patients

Background: Sickle cell disease (SCD) is an inherited blood disorder characterized by chronic hemolysis, inflammation, and vaso-occlusive crises (VOC), leading to several complications and reduced life expectancy of affected individuals. Limited effective treatment options are currently available; however, pharmacogenomic (PGx) insights derived from recent genomic findings, particularly in underrepresented populations such as Saudi Arabians, may offer new hope for predicting molecular-guided treatments. This study aimed to identify approved drugs suitable for repurposing based on their interaction with SCD-associated genetic variants and discover novel druggable targets within genetic pathways linked to disease severity by utilizing genome-wide association study (GWAS) data from Saudi SCD patients. Methods: Our PGx analysis used bioinformatic pipelines to evaluate drug-gene interactions and identify potential therapeutic targets to treat SCD based on GWAS data derived from the Saudi population. Selected approved drugs were suggested for repurposing based on their interactions with genes of interest known to impact SCD pathophysiology, using the Drug-Gene Interaction Database (DGIdb 5.0). New drug targets were also proposed based on assessing the simulated pockets of gene products according to the 3D protein structures provided by the protein data bank (PDB) and the AlphaFold database. New molecules with higher druggability scores, estimated based on the DoGSiteScorer database, were predicted to have a higher success rate in developing new SCD treatments. Results: Our analysis identified 78 approved medications that showed potential for repurposing in SCD; this list was narrowed down to 21 candidates based on their safety profiles and interactions with key genetic pathways in SCD. Among them, 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, had high druggability scores. Conclusion: 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.