title: Mining ZINC Database to Discover Potential Phosphodiesterase 9 Inhibitors Using Structure-Based Drug Design Approach.
abstract: In view of the emerging clinical indications for Phosphodiesterase 9 inhibitors e.g. treatment of Alzheimer, diabetes, cancer, and the limited number of its selective inhibitors which possess a single chemical scaffolds, a structure-based approach was undertaken to mine the ZINC database by virtual screening to identify novel PDE9 inhibitors. The database, which was never reported to have been used before for discovery of PDE9 inhibitors, was screened against the ligand binding pocket of the PDE9 complex (PDB:4GH6) using molecular docking programs, MOE and AutoDock Vina in PyRx. Three different scoring functions were used to evaluate the docking poses and scores of the compounds, and the compounds were selected through consensus selection, thus reducing the margin of error in docking. The highest scoring compounds were then selected and purchased for in vitro testing as PDE9 inhibitors and cancer growth inhibitory agents. This led to the discovery of three previously unreported potent PDE 9 inhibitory compounds with two unique chemical scaffolds. Consistent with the role of PDE9 in cancer cell growth, the compounds also inhibited the growth of breast tumor cell lines, MCF-7 and MDA-468 at concentrations comparable to those that inhibited PDE9.
authors.forename: Engi A
authors.initials: EA
authors.lastname: Hassaan
authors.forename: Sara C
authors.initials: SC
authors.lastname: Sigler
authors.forename: Tamer M
authors.initials: TM
authors.lastname: Ibrahim
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Lee
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Cichon
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Gary
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Canzoneri
authors.forename: Gary A
authors.initials: GA
authors.lastname: Piazza
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. ashraf.abadi@guc.edu.eg.
authors.forename: Ashraf H
authors.initials: AH
authors.lastname: Abadi
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001391:Azo Compounds / Q000737:chemistry / Q000494:pharmacology*; D057225:Data Mining; D062126:Databases, Chemical; D015195:Drug Design; D011564:Furocoumarins / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009282:Naphthalenesulfonates / Q000737:chemistry / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001391:Azo Compounds; D011564:Furocoumarins; D008024:Ligands; D009282:Naphthalenesulfonates; D010726:Phosphodiesterase Inhibitors; C000621026:ZINC18192594; C000621025:ZINC2120735; C000621024:ZINC3954010; D015105:3',5'-Cyclic-AMP Phosphodiesterases