Computational investigation of quinazoline derivatives as Keap1 inhibitors for Alzheimer's disease

Abstract

The Keap1-Nrf2-ARE pathway is crucial in the antioxidant defense mechanism. The Keap1-Nrf2-ARE pathway has become an important target for the development of potent therapeutic agents for numerous diseases. Keap1-Nrf2 protein inhibitors are electrophilic species that covalently bind with the sulfhydryl group of a cysteine residue of Keap1, which results in modification in cysteine residue. In this in-silico research, we investigated the Keap1 inhibitory potential of 99 quinazoline derivatives by molecular docking investigation. The ligand molecules were extracted from the ZINC15 database in sdf format. The pdb format Keap1 protein with PDBID: 4ZY3 was downloaded from RCSB (https://www.rcsb.org/). Resveratrol was chosen as a standard drug molecule for molecular docking studies to compare the results of test ligands. The in-silico docking study was performed by using AutoDock Vina 1.5.7 software. Out of 99 quinazoline derivatives, 12 derivatives showed the best binding energy towards Keap1. Thus, the top 12 quinazoline derivatives were further screened for their ADME profiling, and bioactivity assessment. The molecular docking study revealed that trifluoromethyl substituted quinazoline derivatives S91 and S44 had the best binding energy of −9.1 kcal/mol and −9.0 kcal/mol respectively (better than reference drug Resveratrol, ΔG = −8.1 kcal/mol) at the KELCH binding pocket of Keap1. Compound S91 formed a conventional hydrogen bond with Val (418, 464,512), Ala (366, 466, 607), and Gly (419,511). All 12 derivatives were found to possess drug likeliness properties. For this result, it can be concluded that quinazoline derivatives can be developed as new potent Keap1-Nrf2 inhibitors. The in-vivo/in-vitro study is necessary to validate the in-silico results.