Zhang Renxin, Chen Zhiyuan, Li Shuhan, Lv Haohao, Li Jinjun, Yang Naixue, Dai Shaoxing
State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China.
Yunnan Key Laboratory of Primate Biomedical Research, Kunming 650500, China.
Molecules. 2025 Jan 10;30(2):260. doi: 10.3390/molecules30020260.
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 3000 to over 11,000 proteins. Notably, many druggable pockets were found in less studied proteins, suggesting untapped therapeutic opportunities. The results of a pairwise pocket similarity analysis identified 220,312 similar pocket pairs, with 3241 pairs across different protein families, indicating shared drug-binding potential. In addition, 62,077 significant matches were found between druggable pockets and 1872 known drug pockets, highlighting candidates for drug repositioning. We repositioned progesterone to ADGRD1 for pemphigus and breast cancer, as well as estradiol to ANO2 for shingles and medulloblastoma, which were validated via molecular docking. Off-target effects were analyzed to assess the safety of 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.
药物研发面临着巨大的资金和时间挑战，这凸显了采用更高效策略的必要性。本研究使用Fpocket评估了整个人类蛋白质组的可成药性。我们在20255个预测的蛋白质结构中识别出15043个可成药口袋，将估计的可成药蛋白质组从3000种显著扩展到超过11000种蛋白质。值得注意的是，在研究较少的蛋白质中发现了许多可成药口袋，这表明存在尚未开发的治疗机会。成对口袋相似性分析的结果识别出220312对相似口袋对，其中3241对存在于不同蛋白质家族之间，这表明它们具有共同的药物结合潜力。此外，在可成药口袋与1872个已知药物口袋之间发现了62077个显著匹配，突出了药物重新定位的候选对象。我们将孕酮重新定位到用于治疗天疱疮和乳腺癌的ADGRD1，以及将雌二醇重新定位到用于治疗带状疱疹和髓母细胞瘤的ANO2，这些通过分子对接得到了验证。对脱靶效应进行了分析，以评估阿昔替尼等药物的安全性，将新识别的靶点与已知的副作用联系起来。对于阿昔替尼，识别出了127个新靶点，48种已记录的副作用中有46种与这些靶点相关。这些发现证明了口袋相似性在药物重新定位、靶点扩展和改进药物安全性评估方面的实用性，为发现现有药物的新适应症和副作用提供了新途径。
