title: A rational approach to elucidate human monoamine oxidase molecular selectivity.
abstract: Designing highly selective human monoamine oxidase (hMAO) inhibitors is a challenging goal on the road to a more effective treatment of depression and anxiety (inhibition of hMAO-A isoform) as well as neurodegenerative diseases (inhibition of hMAO-B isoform). To uncover the molecular rationale of hMAOs selectivity, two recently prepared 2H-chromene-2-ones, namely compounds 1 and 2, were herein chosen as molecular probes being highly selective toward hMAO-A and hMAO-B, respectively. We performed molecular dynamics (MD) studies on four different complexes, cross-simulating one at a time the two hMAO-isoforms (dimer embedded in a lipid bilayer) with the two considered probes. Our comparative analysis on the obtained 100ns trajectories discloses a stable H-bond interaction between 1 and Gln215 as crucial for ligand selectivity toward hMAO-A whereas a water-mediated interaction might explain the observed hMAO-B selectivity of compound 2. Such hypotheses are further supported by binding free energy calculations carried out applying the molecular mechanics generalized Born surface area (MM-GBSA) method and allowing us to evaluate the contribution of each residue to the observed isoform selectivity. Taken as whole, this study represents the first attempt to explain at molecular level hMAO isoform selectivity and a valuable yardstick for better addressing the design of new and highly selective MAO inhibitors.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari 'Aldo Moro', Via Orabona, 4, 70126 Bari, Italy.
authors.forename: Giuseppe Felice
authors.initials: GF
authors.lastname: Mangiatordi
authors.affiliation: Institut de Recherche de Chimie Paris CNRS Chimie ParisTech, PSL Research University, 11 rue P. et M. Curie, F-75005 Paris 05, France.
authors.forename: Domenico
authors.initials: D
authors.lastname: Alberga
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari 'Aldo Moro', Via Orabona, 4, 70126 Bari, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pisani
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari 'Aldo Moro', Via Orabona, 4, 70126 Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Gadaleta
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari 'Aldo Moro', Via Orabona, 4, 70126 Bari, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Trisciuzzi
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari 'Aldo Moro', Via Orabona, 4, 70126 Bari, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Farina
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Piazza Università 1, Perugia 06123, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carotti
authors.affiliation: Physics Department, University of Trento, via Sommarive 14 Povo, Trento 38123, Italy; Trento Institute for Fundamental Physics and Applications (INFN-TIFPA), via Sommarive 14 Povo, Trento 38123, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Lattanzi
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari 'Aldo Moro', Via Orabona, 4, 70126 Bari, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari 'Aldo Moro', Via Orabona, 4, 70126 Bari, Italy. Electronic address: orazio.nicolotti@uniba.it.
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D056004:Molecular Dynamics Simulation; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry*; D020033:Protein Isoforms / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008996:Monoamine Oxidase Inhibitors; D020033:Protein Isoforms; D008995:Monoamine Oxidase
keywords: Coumarin derivatives; Drug design; MAO; MM-GBSA; Molecular dynamics; Molecular selectivity