TY - JOUR
T1 - Molecular topology as novel strategy for discovery of drugs with Aβ lowering and anti-aggregation dual activities for Alzheimer's disease
AU - Wang, Jun
AU - Land, David
AU - Ono, Kenjiro
AU - Galvez, Jorge
AU - Zhao, Wei
AU - Vempati, Prashant
AU - Steele, John W.
AU - Cheng, Alice
AU - Yamada, Masahito
AU - Levine, Samara
AU - Mazzola, Paolo
AU - Pasinetti, Giulio M.
PY - 2014/3/26
Y1 - 2014/3/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84899971377&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0092750
DO - 10.1371/journal.pone.0092750
M3 - Article
C2 - 24671215
AN - SCOPUS:84899971377
SN - 1932-6203
VL - 9
JO - PLoS ONE
JF - PLoS ONE
IS - 3
M1 - e92750
ER -