Single crystal X-ray, DFT, molecular dynamic simulations, and biological evaluation of 3-OH pyrrolidine derivative VA10 from alkaloid vasicine for BACE1 inhibition

Abstract

Alzheimer's is a progressive neurodegenerative disease with amyloid-beta peptide deposition that impairs memory and cognitive decline. Due to lack of effective treatment for Alzheimer's disease (AD), there is an interest in finding novel compounds to treat AD. The alkaloid vasicine derivative VA10 inhibited cholinesterases and amyloid beta aggregation in Alzheimer induced rats and showed multi-target activity in treating AD. Therefore, the present study uses single-crystal X-ray and DFT studies to evaluate the properties of VA10′s physicochemical properties, reactivity, and stability. Further, the scaffold VA10 was assessed through in silico, in vitro BACE1 inhibition, and in vivo CNS toxicity experiments. The VA10 Hirshfeld surface analysis and fingerprint plots were determined to understand intra and intermolecular interactions. Furthermore, HOMO-LUMO, UV, and IR studies investigated the electrical and vibrational characteristics. The molecular docking and molecular dynamics simulation studies revealed that compound VA10 formed key interactions with active site amino acid residues and well resided at the BACE1 active site. The VA10 was found to be a potent BACE1 inhibitor and showed no sign of toxicity in rats up to 50 mg/kg. The study identifies VA10, a vasicine derivative, as a possible BACE1 inhibitor in treating Alzheimer's disease. Furthermore, comparing experimental and theoretical results may be beneficial in evaluating VA10′s molecular interactions and reactivity.