CADD-DRIVEN DESIGN OF MERIDIANIN ANALOGUES AS DUAL GSK-3Β AND DYRK1A INHIBITORS FOR NEUROPROTECTION AND COGNITIVE ENHANCEMENT

In the competitive field of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, this research offers a new family of dual-targeted directed ligands, all centered on a unique 2-aminopyrimidine-indole scaffold, derived from marine meridianins. The study employed a structure-based design and synthesis of inhibitors for GSK-3β and DYRK1A kinases, assembling a logical family of 40 ligands via computer screening for drug-likeness according to Lipinski’s Rule of Five (Molinspiration) and prediction of kinase inhibition potential with PASS prediction methods. The study’s validity is further evidenced by molecular docking tests, where two kinases were employed to make predictions, and 80 docking runs were conducted with AutoDock to confirm the predictions. The study’s results reveal that the new family of ligands has shown higher activity than that of the standard compound, indirubicin-3-monoxime. Out of the family, M16 and M32 emerged as the best dual inhibitors, providing the best docking scores, where -10.05 and -10.20 kcal/mol are for GSK-3β, and -8.62 and -9.37 kcal/mol are for DYRK1A kinases, respectively. ADME and toxicity prediction, carried out with ADMETlab 2.0, revealed excellent blood-brain barrier permeability and positive pharmacokinetics with acceptable toxicity, providing a rationale for further research into more potent neuroprotective agents in the field of neurodegenerative diseases research.