Design, Molecular Docking, and ADMET Evaluation of Pyrazoline-Pyridine Derivatives as Dual-Target Ligands for Glucokinase (1V4S) and CDK5 (1UNL)

Abstract

The development of dual-target ligands is an emerging strategy in medicinal chemistry to address complex diseases. This study aimed to evaluate six pyrazoline-pyridine derivatives (5A-5F) as potential dual-target ligands for Glucokinase (1V4S) and Cyclin-Dependent Kinase 5 (CDK5, 1UNL). Molecular docking was performed using AutoDock4 to assess binding affinity and interactions profiles, following validation of the docking protocol (RMSD < 2 Å). The results showed that compound 5F exhibited the strongest binding affinity toward Glucokinase (-10.96 kcal/mol) and high affinity toward CDK5 (-8.34 kcal/mol), forming key interactions with residues Thr65 and Arg63 (Glucokinase) as well as Asn144, and Lys33 (CDK5). ADMET prediction indicated that all compounds comply with Lipinski’s rule and exhibit high gastrointestinal absorption. However, most compounds were predicted to inhibit multiple CYP enzymes and show potential hepatotoxicity, highlighting the need for further optimization. Structure-activity relationship (SAR) analysis revealed that the pyrazoline scaffold contributes to molecular flexibility, while the pyridine ring enhances hydrogen bonding and hydrophobic interactions. Overall, compound 5F is identified as the most promising candidate for further investigation as a dual-target ligand.