Chemoinformatics Profiling of the Chromone Nucleus as a MAO-B/A2AAR Dual Binding Scaffold

Title:Chemoinformatics Profiling of the Chromone Nucleus as a MAO-B/A2AAR Dual Binding Scaffold

Volume: 15 Issue: 8

Author(s): Maykel Cruz-Monteagudo, Fernanda Borges*, M.Natalia D. S. Cordeiro, Aliuska Morales Helguera, Eduardo Tejera, Cesar Paz-y-Mino, Aminael Sanchez-Rodriguez, Yunier Perera-Sardina and Yunierkis Perez-Castillo*

Affiliation:

• CIQUP/Departamento de Quimica e Bioquimica, Faculdade de Ciencias, Universidade do Porto, Porto 4169-007,Portugal

• Departamento de Quimica. Universidad Tecnica Particular de Loja. Loja,Ecuador

Keywords: A2A adenosine receptor, chemoinformatics, chromones, dual-target binder, monoamine oxidase B, parkinson's disease.

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.

Conclusion: 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.

Cite this article as:

Cruz-Monteagudo Maykel, Borges Fernanda*, Cordeiro D. S. M.Natalia , Helguera Morales Aliuska, Tejera Eduardo, Paz-y-Mino Cesar, Sanchez-Rodriguez Aminael, Perera-Sardina Yunier and Perez-Castillo Yunierkis*, Chemoinformatics Profiling of the Chromone Nucleus as a MAO-B/A2AAR Dual Binding Scaffold, Current Neuropharmacology 2017; 15 (8) . https://dx.doi.org/10.2174/1570159X15666170116145316