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Polypyrimidine tract-binding protein 1 (PTBP1) is a critical regulatory target in cancers and neurological disorders. However, the development of its small-molecule inhibitors has been hampered by the lack of traditional druggable pockets on its RNA-binding domains. This study employed a computer-aided drug design (CADD) strategy focusing on a dynamic binding pocket mediated by the flexible linker3 within the PTBP1 RBD3/4 domain. A commercial library containing approximately 1.6 million compounds was subjected to structure-based virtual screening. Following initial filtering based on lead-likeness rules and subsequent molecular docking, 14 candidate compounds were synthesized. Their binding activities were experimentally validated using prokaryotically expressed and purified PTBP1-RBD3/4 recombinant protein via bio-layer interferometry (BLI). Six compounds with micromolar affinity were identified, among which C17414 exhibited the highest binding affinity (KD = 1.6 µmol·L-1). Molecular docking analysis revealed that C17414 efficiently occupies the target pocket through multiple interactions, including hydrogen bonds, salt bridges, π-π stacking and hydrophobic interactions. Systematic ADMET (absorption, distribution, metabolism, excretion and toxicity) property predictions indicated that C17414 and C7485 possess a favorable balance of lipophilicity, polar surface area and membrane permeability, suggesting promising drug-likeness and potential for central nervous system drug development. This work not only discovers a series of high-affinity PTBP1 inhibitor hits and validates the feasibility of targeting its dynamic pocket but also lays a solid foundation for developing novel therapies against PTBP1.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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