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

• Published in: Current neuropharmacology 2017-11, Vol.15 (8), p.1117-1135
• Main Authors: Cruz-Monteagudo, Maykel, Borges, Fernanda, Cordeiro, M.Natalia D. S., Helguera, Aliuska Morales, Tejera, Eduardo, Paz-y-Mino, Cesar, Sanchez-Rodriguez, Aminael, Perera-Sardina, Yunier, Perez-Castillo, Yunierkis
• Format: Article
• Language: English
• Subjects: Adenosine A2 Receptor Antagonists - chemistry; Adenosine A2 Receptor Antagonists - therapeutic use; Amine oxidase (flavin-containing); Animals; Antagonists; Caffeine; Chromones - chemistry; Data processing; Decision making; Drug discovery; Humans; Molecular Docking Simulation; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - therapeutic use; Movement disorders; Neurodegeneration; Neurodegenerative diseases; Parkinson Disease - drug therapy; Parkinson's disease; Protein Binding - drug effects; Receptor, Adenosine A2A - metabolism; Structure-Activity Relationship
• ISSN: 1570-159X; 1875-6190
• DOI: 10.2174/1570159X15666170116145316

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.