Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors
文献类型：期刊论文
| 作者 | Liu, Jiayuan3; Zhang, Xianglei3; Chen, Guofeng2,3; Shao, Qiang3 ; Zou, Yi3; Li, Zhewen2,3; Su, Haixia3; Li, Minjun1; Xu, Yechun2,3,4
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2023-12-15 |
| 卷号 | 262页码:14 |
| 关键词 | Phosphodiesterase-4 (PDE4) PDE5 Inhibitor Drug repurposing Crystal structure Structure -guided optimization |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2023.115893 |
| 通讯作者 | Xu, Yechun(ycxu@simm.ac.cn) |
| 英文摘要 | Phosphodiesterase-4 (PDE4) and PDE5 responsible for the hydrolysis of intracellular cAMP and cGMP, respectively, are promising targets for therapeutic intervention in a wide variety of diseases. Here, we report the discovery of novel, drug-like PDE4 inhibitors by performing a high-throughput drug repurposing screening of 2560 approved drugs and drug candidates in clinical trial studies. It allowed us to identify eight potent PDE4 inhibitors with IC50 values ranging from 0.41 to 2.46 mu M. Crystal structures of PDE4 in complex with four compounds, namely ethaverine hydrochloride (EH), benzbromarone (BBR), CX-4945, and CVT-313, were further solved to elucidate molecular mechanisms of action of these new inhibitors, providing a solid foundation for optimizing the inhibitors to improve their potency as well as selectivity. Unexpectedly, selectivity profiling of other PDE subfamilies followed by crystal structure determination revealed that CVT-313 was also a potent PDE5 inhibitor with a binding mode similar to that of tadalafil, a marketed PDE5 inhibitor, but distinctively different from the binding mode of CVT-313 with PDE4. Structure-guided modification of CVT-313 led to the discovery of a new inhibitor, compound 2, with significantly improved inhibitory activity as well as selectivity towards PDE5 over PDE4. Together, these results highlight the utility of the drug repurposing in combination with structure -based drug design in identifying novel inhibitors of PDE4 and PDE5, which provides a prime example for efficient discovery of drug-like hits towards a given target protein. |
| WOS关键词 | PROTEIN-KINASE CK2 ; PHOSPHODIESTERASE-4 INHIBITOR ; ANTIINFLAMMATORY ACTIVITY ; ETHAVERINE HYDROCHLORIDE ; MODEL ; INTEGRATION ; SILDENAFIL ; EXPRESSION ; BENEFITS ; ISOFORMS |
| 资助项目 | National Natural Science Foundation of China[22277130] ; National Natural Science Foundation of China[32071248] ; Science and Technology Commission of Shanghai Municipality[LG-QS-202205-02] ; Lingang Laboratory ; [22YF1457300] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001106139200001 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/308158]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Xu, Yechun |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Synchrotron Radiat Facil, Shanghai Adv Res Inst, Shanghai 201210, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liu, Jiayuan,Zhang, Xianglei,Chen, Guofeng,et al. Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,262:14. |
| APA | Liu, Jiayuan.,Zhang, Xianglei.,Chen, Guofeng.,Shao, Qiang.,Zou, Yi.,...&Xu, Yechun.(2023).Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,262,14. |
| MLA | Liu, Jiayuan,et al."Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 262(2023):14. |
入库方式： OAI收割
来源：上海药物研究所
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