title: Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.
abstract: Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.
authors: School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.).
authors: Manna
authors: M
authors: Huang
authors: School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.).
authors: Yongxian
authors: Y
authors: Shao
authors: School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.).
authors: Jianying
authors: J
authors: Hou
authors: School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.).
authors: Wenjun
authors: W
authors: Cui
authors: School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.).
authors: Beibei
authors: B
authors: Liang
authors: School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.).
authors: Yingchun
authors: Y
authors: Huang
authors: School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.).
authors: Zhe
authors: Z
authors: Li
authors: School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.).
authors: Yinuo
authors: Y
authors: Wu
authors: School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.).
authors: Xinhai
authors: X
authors: Zhu
authors: School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.).
authors: Peiqing
authors: P
authors: Liu
authors: School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.) hke@med.unc.edu luohb77@mail.sysu.edu.cn ceswyq@mail.sysu.edu.cn.
authors: Yiqian
authors: Y
authors: Wan
authors: School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.) hke@med.unc.edu luohb77@mail.sysu.edu.cn ceswyq@mail.sysu.edu.cn.
authors: Hengming
authors: H
authors: Ke
authors: School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.) hke@med.unc.edu luohb77@mail.sysu.edu.cn ceswyq@mail.sysu.edu.cn.
authors: Hai-Bin
authors: HB
authors: Luo
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D001682:Biological Availability; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008969:Molecular Sequence Data; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D055503:Protein Multimerization; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
chemical_list: D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C116137:PDE9A protein, human