posted on 2018-05-18, 00:00authored byNguyen
Quoc Thai, Zuzana Bednarikova, Miroslav Gancar, Huynh Quang Linh, Chin-Kun Hu, Mai Suan Li, Zuzana Gazova
We
have probed small molecule compound CID 9998128 as a potential
multitarget drug for the Alzheimer’s disease (AD) using in silico and in vitro experiments. By
all-atom simulation and molecular mechanics Poisson–Boltzmann
surface area (MM-PBSA) method, we have demonstrated that this compound
strongly binds to both amyloid β42 (Aβ42) fibrils
and β-secretase, and the van der Waals interaction dominates
over the electrostatic interaction in binding affinity. A detailed
analysis at the atomic level revealed that indazole in CID 99998128
structure made a major contribution to instability of all studied
complexes. In vitro experiments have shown that CID
9998128 inhibits the Aβ42 amyloid fibrillization
and is capable to clear Aβ42 fibrils. Moreover, the
compound dose-dependently decreases β-site amyloid precursor
protein cleaving enzyme (BACE-1) activity with EC50 value
in micromolar range. Thus, our study has revealed that CID 9998128
is a good candidate for AD treatment through preventing production
of Aβ peptides and degrading their aggregates. For drug design,
we predict that the chemical structure of potent AD multitarget inhibitors
should not contain indazole.