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* Pages 1117 - 1135 ( 19 )
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.
A2A adenosine receptor, chemoinformatics, chromones, dual-target binder, monoamine oxidase B, parkinson's disease.
CIQUP/Departamento de Quimica e Bioquimica, Faculdade de Ciencias, Universidade do Porto, Porto 4169-007, CIQUP/Departamento de Quimica e Bioquimica, Faculdade de Ciencias, Universidade do Porto, Porto 4169-007, REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Molecular Simulation and Drug Design Group, Centro de Bioactivos Quimicos (CBQ), Universidad Central “Marta Abreu” de Las Villas, Santa Clara, 54830, Instituto de Investigaciones Biomedicas (IIB), Universidad de Las Americas, 170513 Quito, Instituto de Investigaciones Biomedicas (IIB), Universidad de Las Americas, 170513 Quito, Departamento de Ciencias Naturales, Universidad Tecnica Particular de Loja, Calle Paris S/N, EC1101608 Loja, Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Santiago de Chile, Departamento de Quimica. Universidad Tecnica Particular de Loja. Loja