title: Structural insights into monoamine oxidase inhibitory potency and selectivity of 7-substituted coumarins from ligand- and target-based approaches.
abstract: A new series of 3-, 4-, 7-polysubstituted coumarins have been designed and evaluated for their monoamine oxidase A and monoamine oxidase B (MAO-A and MAO-B) inhibitory potency. Substituents at position 7 consisted of a bridge of different physicochemical nature linking a phenyl ring to the coumarin scaffold. Structure-affinity and structure-selectivity relationships, derived through CoMFA-GOLPE and docking studies, revealed the key physicochemical interactions responsible for the observed MAO-B and MAO-A inhibitory potency and suggested the main structural determinants for high selectivity toward one of the two enzymatic isoforms. The predictive power of our models was proved with the design of a new inhibitor demonstrating an outstanding MAO-B affinity (pIC50 = 8.29) and the highest MAO-B selectivity (DeltapIC50 = 3.39) within the entire series of ligands examined herein.
authors.affiliation: Dipartimento Farmaco-Chimico, Università di Bari, Via Orabona 4, 70125 Bari, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.forename: Francesco
authors.initials: F
authors.lastname: Leonetti
authors.forename: Andrea
authors.initials: A
authors.lastname: Carotti
authors.forename: Angelo Danilo
authors.initials: AD
authors.lastname: Favia
authors.forename: Ramón
authors.initials: R
authors.lastname: Soto-Otero
authors.forename: Estefanía
authors.initials: E
authors.lastname: Méndez-Alvarez
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D000818:Animals; D001665:Binding Sites; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry; D007527:Isoenzymes / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013237:Stereoisomerism
chemical_list: D003374:Coumarins; D007527:Isoenzymes; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase