Compound CID 9998128 Is a Potential Multitarget Drug for Alzheimer's Disease.

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.