4MD6

Crystal structure of PDE5 in complex with inhibitor 5R

Summary for 4MD6

• Entry DOI: 10.2210/pdb4md6/pdb
• Descriptor: cGMP-specific 3',5'-cyclic phosphodiesterase, SULFATE ION, 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one, ... (6 entities in total)
• Functional Keywords: protein-inhibitor complex, phosphodiesterase, pde5 inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38347.73

Authors

Cui, W.,Huang, M.,Shao, Y.,Luo, H. (deposition date: 2013-08-22, release date: 2014-07-09, Last modification date: 2024-11-20)

Primary citation

Shang, N.N.,Shao, Y.X.,Cai, Y.H.,Guan, M.,Huang, M.,Cui, W.,He, L.,Yu, Y.J.,Huang, L.,Li, Z.,Bu, X.Z.,Ke, H.,Luo, H.B.
Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure.
Biochem Pharmacol, 89:86-98, 2014

PubMed Abstract: Phosphodiesterase-5 (PDE5) inhibitors have been approved for the treatment of erectile dysfunction and pulmonary hypertension, but enthusiasm on discovery of PDE5 inhibitors continues for their potential new applications. Reported here is discovery of a series of new PDE5 inhibitors by structure-based design, molecular docking, chemical synthesis, and enzymatic characterization. The best compound, 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (57), has an IC₅₀ of 17 nM against the PDE5 catalytic domain and good selectivity over other PDE families. The crystal structure of the PDE5 catalytic domain in complex with 57 was determined at 2Å resolution and showed that 57 occupies the same pocket as other PDE5 inhibitors, but has a different binding pattern in detail. On the basis of the binding pattern of 57, a novel scaffold can be proposed as a candidate of PDE inhibitors.

PubMed: 24565909
DOI: 10.1016/j.bcp.2014.02.013

Experimental method

X-RAY DIFFRACTION (2 Å)