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Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter‐Related Pathological Features in Alzheimer's Disease
Author(s) -
Lee Hyuck Jin,
Korshavn Kyle J.,
Nam Younwoo,
Kang Juhye,
Paul Thomas J.,
Kerr Richard A.,
Youn Il Seung,
Ozbil Mehmet,
Kim Kwang S.,
Ruotolo Brandon T.,
Prabhakar Rajeev,
Ramamoorthy Ayyalusamy,
Lim Mi Hee
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201605401
Subject(s) - mechanism (biology) , disease , computational biology , flexibility (engineering) , neuroscience , computer science , biology , medicine , pathology , philosophy , statistics , mathematics , epistemology
To elucidate the involvement of individual and inter‐related pathological factors [i.e., amyloid‐β (Aβ), metals, and oxidative stress] in the pathogenesis of Alzheimer's disease (AD), chemical tools have been developed. Characteristics required for such tool construction, however, have not been clearly identified; thus, the optimization of available tools or new design has been limited. Here, key structural properties and mechanisms that can determine tools’ regulatory reactivities with multiple pathogenic features found in AD are reported. A series of small molecules was built up through rational structural selection and variations onto the framework of a tool useful for in vitro and in vivo metal–Aβ investigation. Variations include: (i) location and number of an Aβ interacting moiety; (ii) metal binding site; and (iii) denticity and structural flexibility. Detailed biochemical, biophysical, and computational studies were able to provide a foundation of how to originate molecular formulas to devise chemical tools capable of controlling the reactivities of various pathological components through distinct mechanisms. Overall, this multidisciplinary investigation illustrates a structure–mechanism‐based strategy of tool invention for such a complicated brain disease.