1. Molecular topology as novel strategy for discovery of drugs with aβ lowering and anti-aggregation dual activities for Alzheimer's disease
- Author
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David Land, Alice Cheng, Prashant Vempati, Jun Wang, Jorge Galvez, John W. Steele, Paolo Mazzola, Giulio Maria Pasinetti, Wei Zhao, Kenjiro Ono, Samara Levine, Masahito Yamada, Wang, J, Land, D, Ono, K, Galvez, J, Zhao, W, Vempati, P, Steele, J, Cheng, A, Yamada, M, Levine, S, Mazzola, P, and Pasinetti, G
- Subjects
Models, Molecular ,Drug Evaluation, Preclinical ,lcsh:Medicine ,Disease ,Protein aggregation ,Bioinformatics ,Biochemistry ,Mechanical Treatment of Specimens ,Animal Cells ,Molecular Cell Biology ,Drug Discovery ,Medicine and Health Sciences ,lcsh:Science ,Topology (chemistry) ,Neurons ,Multidisciplinary ,Drug discovery ,Medicine (all) ,Anti aggregation ,Neurodegenerative Diseases ,Animal Models ,Electroporation ,Treatment Outcome ,Neurology ,Specimen Disruption ,Databases as Topic ,Female ,Molecular topology ,Alzheimer's disease ,Cellular Types ,Research Article ,Drug Research and Development ,Mouse Models ,Mice, Transgenic ,Computational biology ,Biology ,Research and Analysis Methods ,Protein Aggregates ,Model Organisms ,Alzheimer Disease ,Mental Health and Psychiatry ,medicine ,Animals ,Humans ,Pharmacology ,Amyloid beta-Peptides ,Biochemistry, Genetics and Molecular Biology (all) ,lcsh:R ,Biology and Life Sciences ,Proteins ,Computational Biology ,Cell Biology ,DUAL (cognitive architecture) ,medicine.disease ,Disease Models, Animal ,Agricultural and Biological Sciences (all) ,Specimen Preparation and Treatment ,Feasibility Studies ,Dementia ,lcsh:Q ,Clinical Medicine ,Protein Multimerization - Abstract
Background and Purpose: 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. Experimental Approach: We used MT to include multiple bioactive properties that allows for the identification of multifunctional 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. Conclusion and Implications: 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.
- Published
- 2014