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 beta 42 (A beta(42)) fibrils and beta-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 A beta(42) amyloid fibrillization and is capable to clear A beta(42) fibrils. Moreover, the compound dose-dependently decreases beta-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 A beta peptides and degrading their aggregates. For drug design, we predict that the chemical structure of potent AD multitarget inhibitors should not contain indazole.