PI-051 - PHARMACOGENOMIC INSIGHTS INTO REPURPOSING APPROVED DRUGS AND DISCOVERING NOVEL MOLECULES FOR TREATING SICKLE CELL DISEASE.

A. Alghubayshi¹, M. Alshabeeb², D. Wijesinghe³, S. Alshammari⁴, M. AlAwadh⁵; ¹Virginia Commonwealth University / Hail University, Hail University, Saudi Arabia, Saudi Arabia, ²King Abdullah International Medical Research Center, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia, Saudi Arabia, ³Virginia Commonwealth University, Virginia Commonwealth University, USA, VA, USA, ⁴Virginia Commonwealth University, Virginia Commonwealth University, US, ⁵King Abdul-Aziz University, King Abdul-Aziz University - Jeddah, Saudi Arabia.

Background: Sickle cell disease (SCD) is an inherited blood disorder with limited effective treatments. Recent genetic findings in underrepresented populations, such as Saudi Arabians, may enable prediction of molecular-guided treatments. This study aimed to identify potential drug repurposing candidates and novel drug targets using Saudi genome-wide association study (GWAS) data on SCD, focusing on genes potentially linked with SCD severity pathways.

Methods: We analyzed the suitability of specific gene loci as drug targets for SCD based on Saudi GWAS data. Approved drugs were suggested for repurposing based on interactions with genes impacting SCD pathophysiology using the Drug-Gene Interaction Database (DGIdb 5.0). New drug targets were proposed by assessing simulated pockets of gene products using 3D protein structures from the Protein Data Bank and AlphaFold database. New molecules with higher druggability scores, estimated using the DoGSiteScorer database, were predicted to have higher success rates in developing SCD treatments.

Results: We identified 78 approved medications with potential for repurposing in SCD, narrowed to 21 candidates based on safety profiles and interactions with key SCD genetic pathways. Simvastatin, allopurinol, omalizumab, canakinumab, and etanercept emerged as the most promising agents. Novel drug targets within OR gene clusters (OR51V1, OR52A1, OR52A5, OR51B5, OR51S1), TRIM genes, SIDT2, and CADM3 showed high druggability scores.

Conclusion: This study provides a framework for drug repurposing and novel drug discovery in SCD, tailored to the Saudi population. The findings highlight the potential of genetic data to identify targeted therapies, offering a pathway to personalized treatments for SCD patients. Future clinical trials are essential to validate these findings and translate them into practice.