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

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, Yunierkis Perez-Castillo*.

Journal Name: Current Neuropharmacology

Volume 15 , Issue 8 , 2017

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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.

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

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Article Details

VOLUME: 15
ISSUE: 8
Year: 2017
Page: [1117 - 1135]
Pages: 19
DOI: 10.2174/1570159X15666170116145316
Price: $58

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