From Structure to Selectivity: Integrating CADD and AIDD in Rational Medicinal Chemistry Strategies for DYRK1A Inhibitor Discovery.
Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a member of the CMGC kinase family, regulates diverse cellular processes and is implicated in Alzheimer's disease, Down syndrome, cancer, and diabetes. However, the clinical translation of DYRK1A inhibitors remains challenging due to limited selectivity arising from the high structural conservation of the ATP-binding pocket within the DYRK and CMGC kinase families, which represents the primary binding region for most DYRK1A inhibitors. Recent advances in computer-aided drug design (CADD), artificial intelligence-driven drug design (AIDD), and rational design strategies have enabled the discovery of small-molecule DYRK1A inhibitors with improved potency, selectivity, and drug-like properties. These approaches have expanded the structural diversity of DYRK1A inhibitors and provided new strategies to address selectivity and pharmacokinetic limitations. Particular emphasis is placed on how CADD and AIDD have expanded the accessible chemical space, informed structure-guided optimization, and enabled new paradigms for DYRK1A-focused drug discovery.