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

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 MAO-B/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 MAO-B inhibitors and A2AAR antagonists with the potential to act as a disease-modifying therapeutic for Parkinson´s disease.

Rational Design of Multitarget-Directed Ligands: Strategies and Emerging Paradigms

“…Among the validated targets for PD treatment, A 2A adenosine receptor (AR) and MAO-B are two most important ones. 207 Combined with levodopa, MAO-B inhibitors can inhibit dopamine metabolism in the brain and therefore increase the levels of dopamine. Compound 71 is a strong A 2A antagonist.…”

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

“…Furthermore, compound 16 containing a chiral azacyclic amide moiety was considered the molecule with the highest potential to inhibit MAO-B, being also demonstrated in vitro [120]. Cruz-Monteagudo et al conducted a cheminformatics analysis to evaluate the potential of chromone derivatives and analogues as MAO-B inhibitors [121]. Based on the information of several SAR studies, two relevant chromone systems were discovered, compounds 17 and 18 (Figure 16) [121].…”

“…Cruz-Monteagudo et al conducted a cheminformatics analysis to evaluate the potential of chromone derivatives and analogues as MAO-B inhibitors [121]. Based on the information of several SAR studies, two relevant chromone systems were discovered, compounds 17 and 18 (Figure 16) [121]. Both compounds displayed high affinity towards the enzyme catalytic site (PDB#2V61), as demonstrated by molecular docking [121].…”

“…Based on the information of several SAR studies, two relevant chromone systems were discovered, compounds 17 and 18 (Figure 16) [121]. Both compounds displayed high affinity towards the enzyme catalytic site (PDB#2V61), as demonstrated by molecular docking [121]. The Mladenović research team also developed an extensive in silico methodology to develop novel MAO-B inhibitors using structure-based 3D-QSAR models, built using the structures of known MAO-B inhibitors deposited in the PDB, and as training sets the structures of compounds with a wide-ranging molecular diversity (aminoindans, aromatic amines, aliphatic amines, aryloxybenzenes, coumarins, thiazolidine-2,4-diones, indoline-2,3-diones, 1,4-diphenyl-2-butenes, terpenes, and imidazolines) [122].…”

Editorial: Improving Neuropharmacology using Big Data, Machine Learning and Computational Algorithms

“…Chromones (1-benzopyran-4-ones) are a natural product with therapeutic implications in cancer, diabetes, cancer and inflammatory diseases. In this study, Cruz-Monteagudo presents quantitative chemistry evaluations to assess the effect of chromone derivatives for dual targeting MAO-B/A 2A AR [ 28 ].…”