Wang Jun, Land David, Ono Kenjiro, Galvez Jorge, Zhao Wei, Vempati Prashant, Steele John W, Cheng Alice, Yamada Masahito, Levine Samara, Mazzola Paolo, Pasinetti Giulio M
Department of Neurology, Mount Sinai School of Medicine, New York, New York, United States of America; Geriatric Research, Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, New York New York, United States of America.
Medisyn Technologies, Inc. Minnetonka, Minnesota, United States of America.
PLoS One. 2014 Mar 26;9(3):e92750. doi: 10.1371/journal.pone.0092750. eCollection 2014.
In this study, we demonstrate the use of Molecular topology (MT) in an Alzheimer's disease (AD) drug discovery program. MT uses and expands upon the principles governing the molecular connectivity theory of numerically characterizing molecular structures, in the present case, active anti-AD drugs/agents, using topological descriptors to build models. Topological characterization has been shown to embody sufficient molecular information to provide strong correlation to therapeutic efficacy.
We used MT to include multiple bioactive properties that allows for the identification of multi-functional single agent compounds, in this case, the dual functions of β-amyloid (Aβ) -lowering and anti-oligomerization. Using this technology, we identified and designed novel compounds in chemical classes unrelated to current anti-AD agents that exert dual Aβ lowering and anti-Aβ oligomerization activities in animal models of AD. AD is a multifaceted disease with different pathological features.
Our study, for the first time, demonstrated that MT can provide novel strategy for discovering drugs with Aβ lowering and anti-aggregation dual activities for AD.
在本研究中，我们展示了分子拓扑学（MT）在阿尔茨海默病（AD）药物研发项目中的应用。MT运用并拓展了支配分子结构数值表征的分子连接性理论的原理，在本案例中，即使用拓扑描述符构建模型来研究活性抗AD药物/药剂。拓扑表征已被证明能够体现足够的分子信息，从而与治疗效果建立强相关性。
我们使用MT纳入多种生物活性特性，以鉴定多功能单剂化合物，在此案例中即具有降低β-淀粉样蛋白（Aβ）和抗寡聚化的双重功能。利用该技术，我们在与当前抗AD药物无关的化学类别中鉴定并设计了新型化合物，这些化合物在AD动物模型中具有降低Aβ和抗Aβ寡聚化的双重活性。AD是一种具有不同病理特征的多方面疾病。
我们的研究首次证明，MT可为发现具有降低Aβ和抗聚集双重活性的AD药物提供新策略。
