Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands To Combat Neurodegenerative Disorders
Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands To Combat Neurodegenerative Disorders
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DOI：
10.1002/cmdc.201500418
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发表时间：
2016-06-20
期刊：
影响因子：
3.4
通讯作者：
Decker, Michael
中科院分区：
文献类型：
--
作者：
Dolles, Dominik;Nimczick, Martin;Decker, Michael
将丁酰胆碱酯酶（BChE）抑制剂的药效团模型应用于人大麻素亚型2受体（hCB（2）R）激动剂，并验证其作为相应双作用化合物的第一代先导化合物。各种衍生物的设计、合成和药理学评价导致将氨基苯并咪唑鉴定为第二代先导化合物，其对两个靶点具有微摩尔或亚微摩尔活性，并且分别对hCB（1）和AChE具有优异的选择性。通过在活性hCB（2）R模型上应用分子动力学（MD）、在hBChE上沿着对接和MD，对第一代和第二代先导结构进行了计算研究，使得能够在蛋白质水平上解释它们的结合谱，并为进一步优化开辟了道路。可以获得具有“平衡的”亲和力和优异选择性的双作用化合物，其代表用于治疗神经退行性疾病中发生的认知和病理生理损伤的先导物。
A pharmacophore model for butyrylcholinesterase (BChE) inhibitors was applied to a human cannabinoid subtype 2 receptor (hCB(2)R) agonist and verified it as a first-generation lead for respective dual-acting compounds. The design, synthesis, and pharmacological evaluation of various derivatives led to the identification of aminobenzimidazoles as second-generation leads with micro-or sub-micromolar activities at both targets and excellent selectivity over hCB(1) and AChE, respectively. Computational studies of the first-and second-generation lead structures by applying molecular dynamics (MD) on the active hCB(2)R model, along with docking and MD on hBChE, has enabled an explanation of their binding profiles at the protein levels and opened the way for further optimization. Dualacting compounds with "balanced" affinities and excellent selectivities could be obtained that represent leads for treatment of both cognitive and pathophysiological impairment occurring in neurodegenerative disorders.