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.
