Molecular Docking Study for Phenazine Derivative Compounds: Cholinesterases and Alzheimer’s disease

Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no definitive treatment to date. According to the cholinergic hypothesis, decreased acetylcholine (ACh) levels contribute to the cognitive symptoms of the disease. Therefore, inhibition of AChE and BChE enzymes is an important strategy in next-generation drug design. In this study, the inhibitory potentials of four phenazine-derived dyes (Safranin-O, Phenosafranine, Pyocyanine and Janus Green B) on AChE and BChE enzymes were evaluated by molecular docking method. Material and Methods: Ligand structures were obtained from PubChem database and energy minimization was performed using MMFF94 force field with Avogadro software. The structures of target proteins, human AChE (PDB: 4M0E) and BChE (PDB: 6QAA), were obtained from RCSB Protein Data Bank and preprocessed to make them ready for docking analyses. Molecular docking analyses were performed with AutoDock Vina (v1.2.5). The complexes obtained were analyzed with Discovery Studio to evaluate binding energies and interaction types. Results: Janus Green B showed the highest binding score for AChE (–9.2 kcal/mol). The strongest binding for BChE was obtained with Safranin-O (–9.1 kcal/mol). The interaction of Phenosafranine with BChE (–8.9 kcal/ mol) is also remarkable. Molecular interaction analyses showed that aromatic residues such as TRP286, TYR341 and TYR124 for AChE and residues such as TRP82, PHE329 and HIS438 for BChE play a central role in ligand binding. All ligands exhibited hydrogen bonds, π-alkyl and electrostatic interactions in the active sites of the enzymes. The findings of the study show that phenazine-derived dyes, especially Janus Green B and Phenosafranine, exhibit strong binding to AChE and BChE enzymes. These molecules can be evaluated among the new inhibitor candidates to be developed against Alzheimer’s disease. Although the findings are based on in silico data, they should be supported by further in vitro and in vivo studies for biological validity. Keywords: Alzheimer’s disease, phenazine, cholinesterase inhibition, acetylcholinesterase, butyrylcholinesterase