Proteome-Wide Identification and Comparison of Drug Pockets for Discovering New Drug Indications and Side Effects
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 expand...
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MDPI AG
2025-01-01
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| author | Renxin Zhang Zhiyuan Chen Shuhan Li Haohao Lv Jinjun Li Naixue Yang Shaoxing Dai |
| author_facet | Renxin Zhang Zhiyuan Chen Shuhan Li Haohao Lv Jinjun Li Naixue Yang Shaoxing Dai |
| author_sort | Renxin Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4c8623efbcfd49deb9ba144344adf516 |
| institution | Kabale University |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj-art-4c8623efbcfd49deb9ba144344adf5162025-01-24T13:43:18ZengMDPI AGMolecules1420-30492025-01-0130226010.3390/molecules30020260Proteome-Wide Identification and Comparison of Drug Pockets for Discovering New Drug Indications and Side EffectsRenxin Zhang0Zhiyuan Chen1Shuhan Li2Haohao Lv3Jinjun Li4Naixue Yang5Shaoxing Dai6State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, ChinaState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, ChinaState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, ChinaState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, ChinaState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, ChinaState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, ChinaState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, ChinaDrug 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.https://www.mdpi.com/1420-3049/30/2/260druggabilityproteomedrug repurposingside effects predictiondrug–protein interactions |
| spellingShingle | Renxin Zhang Zhiyuan Chen Shuhan Li Haohao Lv Jinjun Li Naixue Yang Shaoxing Dai Proteome-Wide Identification and Comparison of Drug Pockets for Discovering New Drug Indications and Side Effects Molecules druggability proteome drug repurposing side effects prediction drug–protein interactions |
| title | Proteome-Wide Identification and Comparison of Drug Pockets for Discovering New Drug Indications and Side Effects |
| title_full | Proteome-Wide Identification and Comparison of Drug Pockets for Discovering New Drug Indications and Side Effects |
| title_fullStr | Proteome-Wide Identification and Comparison of Drug Pockets for Discovering New Drug Indications and Side Effects |
| title_full_unstemmed | Proteome-Wide Identification and Comparison of Drug Pockets for Discovering New Drug Indications and Side Effects |
| title_short | Proteome-Wide Identification and Comparison of Drug Pockets for Discovering New Drug Indications and Side Effects |
| title_sort | proteome wide identification and comparison of drug pockets for discovering new drug indications and side effects |
| topic | druggability proteome drug repurposing side effects prediction drug–protein interactions |
| url | https://www.mdpi.com/1420-3049/30/2/260 |
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