Computer-aided discovery of triazolothiadiazoles as DYRK1A-targeted neuroprotective agents.

ABSTRACT: Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a promising target for drug discovery against neurological diseases. So far, no DYRK1A inhibitor has been approved for clinical use, partly due to the lack of effective and safe chemotypes. In this study, by using a computer-aided drug design strategy and DYRK1A inhibition assay, we were able to identify a novel DYRK1A inhibitor, i.e., compound Y16-5 (Specs ID: AO-365/43472821) with an IC₅₀ value of 0.29 μM. The molecular docking and molecular dynamics simulations uncovered the binding details of compound Y16-5 that included hydrogen bonds with Leu241, Lys188 and Lys167. According to the kinome analysis, compound Y16-5 was highly selective to DYRK1A. Further cell-based assays have shown that

SUBMITTER: Si X 

PROVIDER: S-EPMC12305465 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature