Embelin, a Potent Molecule for Alzheimer's Disease: A Proof of Concept From Blood-Brain Barrier Permeability, Acetylcholinesterase Inhibition and Molecular Docking Studies

Abstract

Embelin is well-known in ethnomedicine and reported to have central nervous system activities. However, there is no report on blood-brain barrier (BBB) permeability of embelin. Here the BBB permeability of embelin was evaluated using in vitro primary porcine brain endothelial cell (PBEC) model of the BBB. Embelin was also evaluated for acetylcholinesterase (AChE) inhibitory activity and docking prediction for interaction with AChE and amyloid beta (Aβ) binding sites. Embelin was found to be non-toxic to the PBECs and did not disturb the PBEC barrier function. The PBECs showed restrictive tight junctions with average transendothelial electrical resistance of 365.37 ± 113.00 Ω.cm 2 , for monolayers used for permeability assays. Permeability assays were conducted from apical-to-basolateral direction (blood-to-brain side). Embelin showed apparent permeability ( P app ) value of 35.46 ± 20.33 × 10 −6 cm/s with 85.53% recovery. In vitro AChE inhibitory assay demonstrated that embelin could inhibit the enzyme. Molecular docking study showed that embelin binds well to active site of AChE with CDOCKER interaction energy of −65.75 kcal/mol which correlates with the in vitro results. Docking of embelin with Aβ peptides also revealed the promising binding with low CDOCKER interaction energy. Thus, findings from this study indicate that embelin could be a suitable molecule to be further developed as therapeutic molecule to treat neurological disorders particularly Alzheimer's disease.

Design, Synthesis and Biological Evaluation of Xanthone Derivatives for Possible Treatment of Alzheimer's Disease Based on Multi‐Target Strategy

“…The active site was selected as an amino acid in the range of 5 Å around the original ligand (donepezil), and the radius of the SBD_Site_Sphere is 15.0 [44] . To validate the docking reliability, co‐crystalized ligand donepezil was first re‐docked to the binding site of AChE [45] . The Cdocker module was used for docking compounds 1 – 4 into the active site of the corresponding protein.…”

“…[44] To validate the docking reliability, co-crystalized ligand donepezil was first re-docked to the binding site of AChE. [45] The Cdocker module was used for docking compounds 1-4 into the active site of the corresponding protein. The interactions with binding pocket residues were analyzed and evaluated by Cdocker interaction energy.…”

Exploring the Chemical Profiles and Biological Values of Two Spondias Species (S. dulcis and S. mombin): Valuable Sources of Bioactive Natural Products

“…The BBB shields the brain from harmful toxins and pathogens, but this protective characteristic is also a hurdle to the entry of therapeutic agents. One of the main reasons why around 98% of newly developed drug candidates fail clinical trial is their inability/poor ability to cross the BBB [ 47 ]. Therefore, assessing the potential of new compounds to cross the BBB is crucial.…”

Discovery of Multitarget-Directed Ligands Against Influenza A Virus From Compound Yizhihao Through a Predictive System for Compound-Protein Interactions

“…Molecular docking, based on the 3D structure of biological proteins obtained by X-ray diffraction, nuclear magnetic resonance data, or homology modeling, is a process that identifies the complementary molecules for a target spatially and electrically. The CDOCKER module is a CHARMm-based docking algorithm (Bhuvanendran et al, 2019), offering full ligand flexibly for high-accuracy docking results of the potential binding mode between ligands and receptors.…”