Chemoinformatics Profiling of the Chromone Nucleus as a MAO-B/A2AAR Dual Binding Scaffold
Chemoinformatics Profiling of the Chromone Nucleus as a MAO-B/A2AAR Dual Binding Scaffold
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DOI：
10.2174/1570159x15666170116145316
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发表时间：
2017-01-01
影响因子：
5.3
通讯作者：
Perez-Castillo, Yunierkis
中科院分区：
文献类型：
--
作者：
Cruz-Monteagudo, Maykel;Borges, Fernanda;Perez-Castillo, Yunierkis
工作背景：在目前的药物发现努力寻找帕金森病（PD）的疾病修饰疗法的背景下，目前的单靶点策略已被证明是低效的。因此，由于PD的多种致病因素，寻找多效药物引起了越来越多的关注。多种证据表明，双重抑制单胺氧化酶B（MAO-B），以及腺苷A（2A）受体（A（2A）AR）阻断，作为一种有前途的方法，以防止涉及PD的神经变性。目前，只有两种化学支架被提出作为潜在的MAO-B抑制剂/（A2）AAR拮抗剂方法：在本研究中，我们进行了一系列的化学信息学分析，以评估和推进色酮核作为MAO-B/（A2）AAR双结合支架的潜力。基于网络相似性图和分子对接研究的SAR数据挖掘分析所提供的信息支持色酮核作为潜在的MAOB/（A2）AAR双结合支架的适用性。此外，开发了基于组融合相似性搜索方法的虚拟筛选工具，用于潜在的MAO-B/（A2）AAR双结合剂候选物的优先级排序。在几个数据融合方案评估，MEAN-SIM和MIN-RANK GFSS方法被证明是有效的虚拟筛选工具。然后，通过使用MIN-RANK和MEAN-SIM GFSS VS方法组装并分选可能富集MAO-B/A2 AAR双重结合色酮衍生物的组合文库。本工作提供的信息和工具代表了在寻找具有良好的双重结合特性的新型色酮衍生物作为MAOB抑制剂和A（2A）的过程中有价值的决策要素。AR拮抗剂有可能作为帕金森病的疾病改善治疗剂。
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.