In silico assisted design synthesis and biological evaluation of novel benzalaniline derivatives comprising 1 3 4 oxadiazole A new scaffold against alzheimers disease

Abstract

Abstract newline In general, oxadiazole and benzalaniline derivatives have shown promising activity against a variety of diseases. Combining these two scaffolds in a single drug candidate is a strategy that has gained increasing interest in multi-targeted drug discovery. This study strives to figure out probable ligands from benzalaniline derivatives comprising 1,3,4-oxadiazole targeted against different targets of Alzheimer s disease using molecular modeling and docking studies. In silco ADME screening was also performed to predict the drug-likeness as well as BBB permeability by the qikprop tool of Schrodinger suit-2023-1 Maestro 13.5.128. The crystallographic structure of molecular targets was obtained from the PDB database (PDB IDs: - Acetylcholinesterase (4EY7), Butyrylcholinesterase (4BDS), monoamine oxidase (2V60) and BASE-1 (7B1P)). Designed ligands showed strong affinity with amino acid residues and their drug-likeness as well as BBB permeability explain their potency to inhibit targets. The chloro-substitution on benzalaniline along with hydroxyl aromatic substitution on oxadiazole has a good binding affinity with the four important receptors selected for this study. 3-Chloro and 3 -hydroxy substituted ligand (R139) shows good affinity with acetylcholinesterase with a binding score of -10.247. If the chloro group on the second position (R114), more effective in butyrylcholinesterase (docking score -7.723). The ligand with 3-chloro and 4 -hydroxy substitution shows a better binding score (-10.545) with MAO-B. All of the suggested compounds were found to lie within the acceptable range of ADME. Molecular dynamic study using desmond tool of Schrödinger software provide detailed insight into ligands behavior at the atomic and molecular levels. This MD simulation study explores that these ligands are thermodynamically stable throughout the simulation time. The in-vitro as well as in-vivo study results of the ligand showed that the ligand containing benzalaniline and 1,3,4-oxadiazole exhibited promising therapeutic.