title: A comparative study of binding affinities for 6,7-dimethoxy-4-pyrrolidylquinazolines as phosphodiesterase 10A inhibitors using the linear interaction energy method.
abstract: The linear interaction energy (LIE) method was used to estimate the free energies of binding for a set of 27 pyrrolidylquinazoline derivatives as phosphodiesterase 10A inhibitors. Twenty-six X-ray crystal structures of phosphodiesterase 10A and two sampling methods, minimization and Hybrid Monte Carlo, were used to assess the affinity models based on the linear interaction energies. The best model was obtained based on the parameters α=0.16 and β=0.04, which represent non-polar and polar interactions, respectively, with a root mean square error (RMSE) of 0.42kcal/mol (R(2)=0.71) and 0.52kcal/mol (R(2)=0.86) for the training and test sets, respectively. In addition, the applicability domain of the model was investigated. After validation of the models, the best model was subsequently used in a virtual screening process, which resulted in a set of optimized compounds. The models developed in this study could be useful as filter for virtual screening and lead optimization processes for phosphodiesterase 10A drug developments.
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
authors.forename: Erik Rosendahl
authors.initials: ER
authors.lastname: Kjellgren
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
authors.forename: Oliver Emil Skytte
authors.initials: OE
authors.lastname: Glue
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Reinholdt
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
authors.forename: Julie Egeskov
authors.initials: JE
authors.lastname: Meyer
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Kongsted
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark. Electronic address: nathan@sdu.dk.
authors.forename: Vasanthanathan
authors.initials: V
authors.lastname: Poongavanam
mesh_terms: D020816:Amino Acid Motifs; D014150:Antipsychotic Agents / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011759:Pyrrolidines / Q000737:chemistry*; D011799:Quinazolines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D014150:Antipsychotic Agents; D008024:Ligands; D010726:Phosphodiesterase Inhibitors; D011759:Pyrrolidines; D011799:Quinazolines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: Binding affinity; Linear interaction energy; Phosphodiesterase 10A; Pyrrolidylquinazoline; Schizophrenia; Virtual screening and applicability domain