Discovery of a Novel Chemotype as DYRK1A Inhibitors against Alzheimer’s disease: Computational Modeling and Biological Evaluation

Abstract

AbstractDual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) plays an essential role in tau and Aβ pathology closely related to Alzheimer’s disease (AD). Accumulative evidence has demonstrated DYRK1A inhibition is able to reduce the pathological features of AD. Nevertheless, there is no approved DYRK1A inhibitors for clinical use as anti-AD drugs. This is somewhat the lack of effective and safe chemotypes of DYRK1A inhibitors. To address this issue, we carried outin silicoscreening,in vitroassays andin vivoefficacy evaluation with the aim to discover a new class of DYRK1A inhibitors for potential treatment of AD. Byin silicoscreening, we selected and purchased 16 potential DYRK1A inhibitors from the Specs chemical library. Among them, compoundQ17(Specs ID: AO-476/40829177) potently inhibited DYRK1A. The hydrogen bonds between compoundQ17and each of three amino acid residues named GLU239, LEU241 and LYS188, were uncovered by molecular docking and molecular dynamics simulation. The cell-based assays showed that compoundQ17could protect SH-SY5Y cells from okadaic acid (OA)-induced injury by targeting DYRK1A. More importantly, compoundQ17significantly improved cognitive dysfunction in 3×Tg-AD mice, ameliorated pathological changes, and reduced the expression of DYRK1A, GSK-3β and GSK-3β (pSer9), attenuated tau hyperphosphorylation and Aβ deposition as well. In summary, our computational modeling strategy is effective to identify novel chemotypes of DYRK1A inhibitors with great potential to treat AD, and the identified compoundQ17in this study is worthy of further study.Graphic Abstract