title: Exploring the PDE5 H-pocket by ensemble docking and structure-based design and synthesis of novel β-carboline derivatives.
abstract: By studying the co-crystal information of interactions between PDE5 and its inhibitors, forty new tetrahydro-β-carbolines based-analogues were synthesized, and tested for their PDE5 inhibition. Some compounds were as active as tadalafil in inhibiting PDE5 and of better selectivity profile particularly versus PDE11A, the nature of the terminal ring and its nitrogen substituent are the main determinants of selectivity. Ensemble docking confirmed the role of H-loop closed conformer in activity versus its occluded and open forms. Conformational studies showed the effect of bulkiness of the terminal ring N-alkyl substituent on the formation of stable enzyme ligands conformers. The difference in potencies of hydantoin and piperazinedione analogues, together with the necessity of C-5/C-6 R-absolute configuration has been revealed through molecular docking.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Main Entrance, Al-Tagmoaa Al-Khames, Cairo 11835, Egypt.
authors.forename: Nermin S
authors.initials: NS
authors.lastname: Ahmed
authors.forename: Amal H
authors.initials: AH
authors.lastname: Ali
authors.forename: Shreen M
authors.initials: SM
authors.lastname: El-Nashar
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Gary
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Fajardo
authors.forename: Heather N
authors.initials: HN
authors.lastname: Tinsley
authors.forename: Gary A
authors.initials: GA
authors.lastname: Piazza
authors.forename: Matthias
authors.initials: M
authors.lastname: Negri
authors.forename: Ashraf H
authors.initials: AH
authors.lastname: Abadi
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry; D049109:Cell Proliferation; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry*; D054659:Diketopiperazines / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D057075:Enzyme Assays; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D007700:Kinetics; D062105:Molecular Docking Simulation; D058986:Phosphodiesterase 5 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D000068581:Tadalafil; D013816:Thermodynamics
chemical_list: D002243:Carbolines; D054659:Diketopiperazines; D006827:Hydantoins; D058986:Phosphodiesterase 5 Inhibitors; D011994:Recombinant Proteins; D000068581:Tadalafil; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C406737:PDE11A protein, human