Exploring Promising Multi-targeted Drug Candidate for Alzheimer’s Disease from Compounds Based on Benzalaniline with 1,3,4-Oxadiazole Skeleton: An In Silico Modeling and Docking Study

In general, oxadiazole and benzalaniline derivatives have shown promising activity against a variety of diseases. Combining these two scaffolds into a single drug candidate is a strategy that has garnered increasing interest in multi-targeted drug discovery. This study aims to identify potential ligands from benzalaniline derivatives containing 1,3,4-oxadiazole, targeting various proteins associated with Alzheimer’s disease through molecular modeling and docking studies. In silico ADME screening was also performed to predict drug-likeness and blood-brain barrier (BBB) permeability, using the QikProp tool from the Schrodinger suit 2023-1 (Maestro 13.5.128). The crystallographic structure of the molecular targets was obtained from the PDB database, specifically Acetylcholinesterase (PDB ID: 4EY7), Butyrylcholinesterase (PDB ID: 4BDS), Monoamine Oxidase (PDB ID: 2V60), and BACE-1 (PDB ID: 7B1P). The designed ligands demonstrated strong affinity with key amino acid residues and their drug-likeness. Along with BBB permeability, it highlights their potential as inhibitors for these targets. In particular, chloro substitution on benzalaniline, combined with hydroxyl aromatic substitution on oxadiazole, exhibited favorable binding affinity with the four receptors selected for this study. A ligand with 3-Chloro and 3’-hydroxy substitution (R139) displayed a strong binding affinity for acetylcholinesterase, with a docking score of -10.247. When the chloro group was positioned at the second site (R114), it was more effective against butyrylcholinesterase, yielding a docking score of -7.723. Furthermore, a ligand with 3-chloro and 4’-hydroxy substitution showed a superior binding score (-10.545) with MAO-B. All proposed compounds fell within the acceptable ADME range (BBB permeability: QPPMDCK value >500; QPlog BB 3 to 1.2). Based on the data presented in this study, the suggested ligands should be considered as potential inhibitors.