<b>Proteome-wide identification and comparison of drug pockets for discovering new drug indications and side effects</b>

Drug development faces significant financial and time challenges, highlighting the need for more efficient strategies. This study evaluated the druggability of the entire human proteome using Fpocket. We identified 15,043 druggable pockets in 20,255 predicted protein structures, significantly expanding the estimated druggable proteome from 3,000 to over 11,000 proteins. Notably, many druggable pockets were found in less-studied proteins, suggesting untapped therapeutic opportunities. Pairwise pocket similarity analysis identified 220,312 similar pocket pairs, with 3,241 pairs across different protein families, indicating shared drug-binding potential. In addition, 62,077 significant matches were found between druggable pockets and 1,872 known drug pockets, highlighting candidates for drug repositioning. We repositioned progesterone to ADGRD1 for pemphigus and breast cancer, and estradiol to ANO2 for shingles and medulloblastoma, which were validated by molecular docking. To assess safety, off-target effects were analyzed for the drugs such as axitinib, linking newly identified targets with known side effects. For axitinib, 127 new targets were identified and 46 out of 48 documented side effects were linked to these targets. These findings demonstrate the utility of pocket similarity in drug repositioning, target expansion, and improved drug safety evaluation, offering new avenues for the discovery of new indications and side effects of existing drugs.