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

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>i.e.</i>, compound Y16-5 (Specs ID: <b>AO-365/43472821</b>) 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 compound Y16-5 could protect human neuroblastoma cell line SH-SY5Y from okadaic acid (OA)-induced injury. In terms of the molecular mechanism, compound Y16-5 decreased tau (pSer396)/tau and Aβ_1-42 protein expression highly related to Alzheimer's disease. Further <i>in vitro</i> druglikeness evaluation has demonstrated that (1) compound Y16-5 was not toxic to SH-SY5Y and HL-7702 cells (CC₅₀ > 100 μM), and (2) compound Y16-5 could permeate the blood-brain-barrier, with a permeability value of 31.52 (×10^-6 cm s^-1). Taken together, we have discovered a potent DYRK1A inhibitor Y16-5 with neuroprotective activity by <i>in silico</i> screening and <i>in vitro</i> bioassays.