title: Understanding the Molecular Determinant of Reversible Human Monoamine Oxidase B Inhibitors Containing 2H-Chromen-2-One Core: Structure-Based and Ligand-Based Derived Three-Dimensional Quantitative Structure-Activity Relationships Predictive Models.
abstract: Monoamine oxidase B (MAO B) catalyzes the oxidative deamination of aryalkylamines neurotransmitters with concomitant reduction of oxygen to hydrogen peroxide. Consequently, the enzyme's malfunction can induce oxidative damage to mitochondrial DNA and mediates development of Parkinson's disease. Thus, MAO B emerges as a promising target for developing pharmaceuticals potentially useful to treat this vicious neurodegenerative condition. Aiming to contribute to the development of drugs with the reversible mechanism of MAO B inhibition only, herein, an extended in silico-in vitro procedure for the selection of novel MAO B inhibitors is demonstrated, including the following: (1) definition of optimized and validated structure-based three-dimensional (3-D) quantitative structure-activity relationships (QSAR) models derived from available cocrystallized inhibitor-MAO B complexes; (2) elaboration of SAR features for either irreversible or reversible MAO B inhibitors to characterize and improve coumarin-based inhibitor activity (Protein Data Bank ID: 2V61 ) as the most potent reversible lead compound; (3) definition of structure-based (SB) and ligand-based (LB) alignment rule assessments by which virtually any untested potential MAO B inhibitor might be evaluated; (4) predictive ability validation of the best 3-D QSAR model through SB/LB modeling of four coumarin-based external test sets (267 compounds); (5) design and SB/LB alignment of novel coumarin-based scaffolds experimentally validated through synthesis and biological evaluation in vitro. Due to the wide range of molecular diversity within the 3-D QSAR training set and derived features, the selected N probe-derived 3-D QSAR model proves to be a valuable tool for virtual screening (VS) of novel MAO B inhibitors and a platform for design, synthesis and evaluation of novel active structures. Accordingly, six highly active and selective MAO B inhibitors (picomolar to low nanomolar range of activity) were disclosed as a result of rational SB/LB 3D QSAR design; therefore, D123 (IC50= 0.83 nM, Ki= 0.25 nM) and D124 (IC50= 0.97 nM, Ki= 0.29 nM) are potential lead candidates as anti-Parkinson's drugs.
authors.affiliation: Kragujevac Center for Computational Biochemistry, Faculty of Science, University of Kragujevac , Radoja Domanovića 12, 34000 Kragujevac, P.O. Box 60, Serbia.
authors.forename: Milan
authors.identifier: 0000-0002-6556-8778
authors.initials: M
authors.lastname: Mladenović
authors.affiliation: Rome Center for Molecular Design, Department of Drug Chemistry and Technologies, Faculty of Pharmacy and Medicine, Rome Sapienza University , P.le A. Moro 5, 00185, Rome Italy.|Alchemical Dynamics srl , 00125 Rome, Italy.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Patsilinakos
authors.affiliation: Rome Center for Molecular Design, Department of Drug Chemistry and Technologies, Faculty of Pharmacy and Medicine, Rome Sapienza University , P.le A. Moro 5, 00185, Rome Italy.|Department of Information Technology, IRBM Science Park , Via Pontina km 30, 600, 00071 Pomezia, Rome, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Pirolli
authors.affiliation: Rome Center for Molecular Design, Department of Drug Chemistry and Technologies, Faculty of Pharmacy and Medicine, Rome Sapienza University , P.le A. Moro 5, 00185, Rome Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sabatino
authors.affiliation: Rome Center for Molecular Design, Department of Drug Chemistry and Technologies, Faculty of Pharmacy and Medicine, Rome Sapienza University , P.le A. Moro 5, 00185, Rome Italy.|Alchemical Dynamics srl , 00125 Rome, Italy.
authors.forename: Rino
authors.identifier: 0000-0001-5399-975X
authors.initials: R
authors.lastname: Ragno
mesh_terms: D001578:Benzopyrans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008567:Membranes, Artificial; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010539:Permeability; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship
chemical_list: D001578:Benzopyrans; D008024:Ligands; D008567:Membranes, Artificial; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase