SAR by kinetics for drug discovery in protein misfolding diseases

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title = "SAR by kinetics for drug discovery in protein misfolding diseases",
abstract = "To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure.activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize starting compounds to curtail A{\^a} oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aβ oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.",
keywords = "Alzheimer's disease, Amyloid beta peptide, Chemical kinetics, Protein aggregation, Protein misfolding",
author = "Sean Chia and Johnny Habchi and Michaels, {Thomas C.T.} and Cohen, {Samuel I.A.} and Sara Linse and Dobson, {Christopher M.} and Knowles, {Tuomas P.J.} and Michele Vendruscolo",
year = "2018",
doi = "10.1073/pnas.1807884115",
language = "English",
volume = "115",
pages = "10245--10250",
journal = "Proceedings of the National Academy of Sciences",
issn = "1091-6490",
publisher = "National Acad Sciences",
number = "41",