title: An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies.
abstract: Selective inhibitors of cyclic nucleotide phosphodiesterase-5 (PDE5) have been used as drugs for treatment of male erectile dysfunction and pulmonary hypertension. An insight into the pharmacophores of PDE5 inhibitors is essential for development of second generation of PDE5 inhibitors, but has not been completely illustrated. Here we report the synthesis of a new class of the sildenafil derivatives and a crystal structure of the PDE5 catalytic domain in complex with 5-(2-ethoxy-5-(sulfamoyl)-3-thienyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (12). Inhibitor 12 induces conformational change of the H-loop (residues 660-683), which is different from any of the known PDE5 structures. The pyrazolopyrimidinone groups of 12 and sildenafil are well superimposed, but their sulfonamide groups show a positional difference of as much as 1.5A. The structure-activity analysis suggests that a small hydrophobic pocket and the H-loop of PDE5 are important for the inhibitor affinity, in addition to two common elements for binding of almost all the PDE inhibitors: the stack against the phenylalanine and the hydrogen bond with the invariant glutamine. However, the PDE5-12 structure does not provide a full explanation to affinity changes of the inhibitors. Thus alternatives such as conformational change of the M-loop are open and further structural study is required.
authors.affiliation: School of Chemistry and Chemical Engineering, Center of Structure Biology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510275, PR China.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.forename: Huanchen
authors.initials: H
authors.lastname: Wang
authors.forename: Howard
authors.initials: H
authors.lastname: Robinson
authors.forename: Jiwen
authors.initials: J
authors.lastname: Cai
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Wan
authors.forename: Hengming
authors.initials: H
authors.lastname: Ke
mesh_terms: D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000068677:Sildenafil Citrate; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human