title: Molecular topology as novel strategy for discovery of drugs with aβ lowering and anti-aggregation dual activities for Alzheimer's disease.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Medisyn Technologies, Inc. Minnetonka, Minnesota, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Land
authors.affiliation: Department of Neurology and Neurobiology of Aging, Kanazawa University, Kanazawa, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Ono
authors.affiliation: Molecular Topology & Drug Design Unit, University of Valencia, Valencia, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Galvez
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Prashant
authors.initials: P
authors.lastname: Vempati
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: Steele
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Alice
authors.initials: A
authors.lastname: Cheng
authors.affiliation: Department of Neurology and Neurobiology of Aging, Kanazawa University, Kanazawa, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Samara
authors.initials: S
authors.lastname: Levine
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mazzola
authors.affiliation: 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.
authors.forename: Giulio M
authors.initials: GM
authors.lastname: Pasinetti
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D019992:Databases as Topic; D004195:Disease Models, Animal; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008822:Mice, Transgenic; D008958:Models, Molecular; D066329:Protein Aggregates; D055503:Protein Multimerization; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D066329:Protein Aggregates