8W4S

Crystal structure of PDE5A in complex with CVT-313

8W4S の概要

• エントリーDOI: 10.2210/pdb8w4s/pdb
• 分子名称: cGMP-specific 3',5'-cyclic phosphodiesterase, MAGNESIUM ION, ZINC ION, ... (5 entities in total)
• 機能のキーワード: pde5a, inhibitor, complex structure, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40581.28

構造登録者

Liu, J.Y.,Li, M.J.,Xu, Y.C. (登録日: 2023-08-24, 公開日: 2023-11-22)

主引用文献

Liu, J.,Zhang, X.,Chen, G.,Shao, Q.,Zou, Y.,Li, Z.,Su, H.,Li, M.,Xu, Y.
Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors.
Eur.J.Med.Chem., 262:115893-115893, 2023

PubMed Abstract: 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 IC values ranging from 0.41 to 2.46 μM. 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.

PubMed: 37918035
DOI: 10.1016/j.ejmech.2023.115893

実験手法

X-RAY DIFFRACTION (1.848 Å)