title: Molecular docking study and development of an empirical binding free energy model for phosphodiesterase 4 inhibitors.
abstract: In the present work, several computational methodologies were combined to develop a model for the prediction of PDE4B inhibitors' activity. The adequacy of applying the ligand docking approach, keeping the enzyme rigid, to the study of a series of PDE4 inhibitors was confirmed by a previous molecular dynamics analysis of the complete enzyme. An exhaustive docking procedure was performed to identify the most probable binding modes of the ligands to the enzyme, including the active site metal ions and the surrounding structural water molecules. The enzyme-inhibitor interaction enthalpies, refined by using the semiempirical molecular orbital approach, were combined with calculated solvation free energies and entropy considerations in an empirical free energy model that enabled the calculation of binding free energies that correlated very well with experimentally derived binding free energies. Our results indicate that both the inclusion of the structural water molecules close to the ions in the binding site and the use of a free energy model with a quadratic dependency on the ligand free energy of solvation are important aspects to be considered for molecular docking investigations involving the PDE4 enzyme family.
authors.affiliation: LASSBio, Laboratório de Avaliação e Síntese de Substãncias Bioativas, Faculdade de Farmácia and Instituto de Química, Universidade Federal do Rio de Janeiro, PO Box 68006, Rio de Janeiro, RJ 21944-910, Brazil.
authors.forename: Fernanda G
authors.initials: FG
authors.lastname: Oliveira
authors.forename: Carlos M R
authors.initials: CM
authors.lastname: Sant'Anna
authors.forename: Ernesto R
authors.initials: ER
authors.lastname: Caffarena
authors.forename: Laurent E
authors.initials: LE
authors.lastname: Dardenne
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4