title: Chemoinformatics Profiling of the Chromone Nucleus as a MAO-B/A2AAR Dual Binding Scaffold.
abstract: BACKGROUND
  In the context of the current drug discovery efforts to find disease modifying therapies for Parkinson's disease (PD) the current single target strategy has proved inefficient. Consequently, the search for multi-potent agents is attracting more and more attention due to the multiple pathogenetic factors implicated in PD. Multiple evidences points to the dual inhibition of the monoamine oxidase B (MAO-B), as well as adenosine A2A receptor (A2AAR) blockade, as a promising approach to prevent the neurodegeneration involved in PD. Currently, only two chemical scaffolds has been proposed as potential dual MAO-B inhibitors/A2AAR antagonists (caffeine derivatives and benzothiazinones).
  
  
  METHODS
  In this study, we conduct a series of chemoinformatics analysis in order to evaluate and advance the potential of the chromone nucleus as a MAO-B/A2AAR dual binding scaffold.
  
  
  RESULTS
  The information provided by SAR data mining analysis based on network similarity graphs and molecular docking studies support the suitability of the chromone nucleus as a potential MAOB/ A2AAR dual binding scaffold. Additionally, a virtual screening tool based on a group fusion similarity search approach was developed for the prioritization of potential MAO-B/A2AAR dual binder candidates. Among several data fusion schemes evaluated, the MEAN-SIM and MIN-RANK GFSS approaches demonstrated to be efficient virtual screening tools. Then, a combinatorial library potentially enriched with MAO-B/A2AAR dual binding chromone derivatives was assembled and sorted by using the MIN-RANK and then the MEAN-SIM GFSS VS approaches.
  
  
  CONCLUSIONS
  The information and tools provided in this work represent valuable decision making elements in the search of novel chromone derivatives with a favorable dual binding profile as MAOB inhibitors and A2AAR antagonists with the potential to act as a disease-modifying therapeutic for Parkinson's disease.
authors.affiliation: CIQUP/Departamento de Quimica e Bioquimica, Faculdade de Ciencias, Universidade do Porto, Porto 4169-007, Portugal.|Instituto de Investigaciones Biomedicas (IIB), Universidad de Las Americas, 170513 Quito, Ecuador.
authors.forename: Maykel
authors.initials: M
authors.lastname: Cruz-Monteagudo
authors.affiliation: CIQUP/Departamento de Quimica e Bioquimica, Faculdade de Ciencias, Universidade do Porto, Porto 4169-007, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
authors.affiliation: REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal.
authors.forename: M Natalia D S
authors.initials: MNDS
authors.lastname: Cordeiro
authors.affiliation: Molecular Simulation and Drug Design Group, Centro de Bioactivos Quimicos (CBQ), Universidad Central "Marta Abreu" de Las Villas, Santa Clara, 54830, Cuba.
authors.forename: Aliuska Morales
authors.initials: AM
authors.lastname: Helguera
authors.affiliation: Instituto de Investigaciones Biomedicas (IIB), Universidad de Las Americas, 170513 Quito, Ecuador.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tejera
authors.affiliation: Instituto de Investigaciones Biomedicas (IIB), Universidad de Las Americas, 170513 Quito, Ecuador.
authors.forename: Cesar
authors.initials: C
authors.lastname: Paz-Y-Mino
authors.affiliation: Departamento de Ciencias Naturales, Universidad Tecnica Particular de Loja, Calle Paris S/N, EC1101608 Loja, Ecuador.
authors.forename: Aminael
authors.initials: A
authors.lastname: Sanchez-Rodriguez
authors.affiliation: Departamento de Ciencias Quimicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Santiago de Chile, Chile.
authors.forename: Yunier
authors.initials: Y
authors.lastname: Perera-Sardina
authors.affiliation: Molecular Simulation and Drug Design Group, Centro de Bioactivos Quimicos (CBQ), Universidad Central "Marta Abreu" de Las Villas, Santa Clara, 54830, Cuba.|Seccion Fisico Quimica y Matematicas, Departamento de Quimica, Universidad Tecnica Particular de Loja, San Cayetano Alto S/N, EC1101608 Loja, Ecuador.
authors.forename: Yunierkis
authors.initials: Y
authors.lastname: Perez-Castillo
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D002867:Chromones / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy*; D011485:Protein Binding / Q000187:drug effects; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D002867:Chromones; D008996:Monoamine Oxidase Inhibitors; D043705:Receptor, Adenosine A2A; D008995:Monoamine Oxidase
keywords: A2A adenosine receptor; chemoinformatics; chromones; dual-target binder; monoamine oxidase B; parkinson's
  disease.