Chemoinformatics profiling of the chromone nucleus as a MAO-B/A2AAR dual binding scaffold

Maykel Cruz-Monteagudo, Fernanda Borges, M. Natália D.S. Cordeiro, Aliuska Morales Helguera, Eduardo Tejera, Cesar Paz-y-Miño, Aminael Sánchez-Rodríguez, Yunier Perera-Sardiña, Yunierkis Perez-Castillo

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1117-1135
Number of pages19
JournalCurrent Neuropharmacology
Volume15
Issue number8
DOIs
Publication statusPublished - 1 Nov 2017
Externally publishedYes

Keywords

  • A adenosine receptor
  • Chemoinformatics
  • Chromones
  • Dual-target binder
  • Monoamine oxidase B
  • Parkinson’s disease

ASJC Scopus subject areas

  • Pharmacology
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Pharmacology (medical)

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