Evaluation of pyrazolopyrimidine derivatives as microtubule affinity regulating kinase 4 inhibitors: Towards therapeutic management of Alzheimer’s disease

Microtubule affinity regulating kinase 4 (MARK4) plays essential role in the tau-assisted regulation of microtubule dynamics. Over expression of MARK4 causes early phosphorylation of Ser262 of tau protein which is essential for microtubule binding. Hyperphosphorylation of tau protein causes the formation of paired helical fragments and neurofibrillary tangles, the hallmarks of Alzheimer’s disease. Targeting the modulation of MARK4 activity is an effective strategy for therapeutic intervention of Alzheimer’s and other MARK4 associated neurodegenerative diseases. Having role of pyrazolopyrimidine derivatives in the therapeutic management of neurodegenerative diseases, we have tried to estimate their binding affinity with the MARK4. We performed in silico screening of 59 pyrazolopyrimidine derivatives against MARK4 and obtained a few best possible inhibitors. Molecular docking-based interaction analysis suggested five potential leads that were further analyzed using molecular dynamics simulations, MM/PBSA, principal component analysis and graph theory based dynamic network analysis to observe structural changes caused due to ligand binding. All these computational analyses suggested that compounds with PubChem IDs: 91895678, 91895679, 91895692, 91145515 and 90794095 may be further exploited to address Alzheimer’s and other neurodegenerative diseases. Communicated by Ramaswamy H. Sarma

微管亲和力调控激酶4（Microtubule affinity regulating kinase 4，MARK4）在tau蛋白辅助调控微管动态平衡的过程中发挥关键作用。MARK4过表达会导致tau蛋白Ser262位点发生早期磷酸化，而该修饰对于tau蛋白结合微管至关重要。tau蛋白的过度磷酸化会引发成对螺旋丝与神经原纤维缠结的形成，二者均为阿尔茨海默病的典型病理特征。靶向调控MARK4活性，是治疗阿尔茨海默病及其他与MARK4相关的神经退行性疾病的有效策略。鉴于吡唑并嘧啶类衍生物在神经退行性疾病治疗中的应用潜力，本研究尝试评估其与MARK4的结合亲和力。我们针对MARK4对59种吡唑并嘧啶类衍生物开展了计算机虚拟筛选，获得了若干潜在强效抑制剂。基于分子对接的相互作用分析筛选出5个潜在先导化合物，随后通过分子动力学模拟、MM/PBSA结合自由能计算、主成分分析以及基于图论的动态网络分析等手段，进一步探究配体结合所引发的蛋白质结构变化。上述所有计算分析结果表明，PubChem编号分别为91895678、91895679、91895692、91145515及90794095的化合物，可作为后续开发阿尔茨海默病及其他神经退行性疾病治疗药物的潜在候选物。本稿件由Ramaswamy H. Sarma转交。