Chemoinformatics Profiling of the Chromone Nucleus as a MAO-B/A(2A)AR Dual Binding Scaffold

• Type: Article in International Scientific Journal
• Date: 2017

Authors

Cruz Monteagudo, M (Author) Other; Fernanda Borges (Author) FCUP; Natalia N D S Cordeiro (Author) FCUP; Helguera, AM (Author) Other; Tejera, E (Author) Other; Paz y Mino, C (Author) Other; Sanchez Rodriguez, A (Author) Other; Perera Sardina, Y (Author) Other; Perez Castillo, Y (Author) Other

Journal

Title: Current Neuropharmacology

Vol. 15

Pages: 1117-1135

ISSN: 1570-159X

Publisher: Bentham Science

Indexing

ISI Web of Knowledge - 6 Citations

Scopus - 6 Citations

Other information

Authenticus ID: P-00N-8JM

DOI: 10.2174/1570159x15666170116145316

Abstract (EN): 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 A(2A) receptor (A(2A)AR) 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/(A2)AAR 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/(A2)AAR 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/ (A2)AAR 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/(A2)AAR 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 A(2A)AR antagonists with the potential to act as a disease-modifying therapeutic for Parkinson 's disease.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 19