Biaryl scaffold-focused virtual screening for anti-aggregatory and neuroprotective effects in Alzheimer’s disease

Abstract

BackgroundAlzheimer’s disease (AD) is a primary cause of dementia in ageing population affecting more than 35 million people around the globe. It is a chronic neurodegenerative disease caused by defected folding and aggregation of amyloid beta (Aβ) protein. Aβ is formed by the cleavage of membrane embedded amyloid precursor protein (APP) by using enzyme ‘transmembrane aspartyl protease, β-secretase’. Inhibition of β-secretase is a viable strategy to prevent neurotoxicity in AD. Another strategy in the treatment of AD is inhibition of acetylcholinesterase. This inhibition reduces the degradation of acetylcholine and temporarily restores the cholinergic function of neurons and improves cognitive function. Monoamine oxidase and higher glutamate levels are also found to be linked with Aβ peptide related oxidative stress. Oxidative stress leads to reduced activity of glutamate synthase resulting in significantly higher level of glutamate in brain. The aim of this study is to perform in silico screening of a virtual library of biaryl scaffold containing compounds potentially used for the treatment of AD. Screening was done against the primary targets of AD therapeutics, acetylcholinesterase, β-secretase (BACE1), Monoamine oxidases (MAO) and N-Methyl-D-aspartate (NMDA) receptor. Compounds were screened for their inhibitory potential by employing molecular docking approach using AutoDock vina. Binding energy scores were embodied in the heatmap to display varies strengths of interactions of the ligands targeting AD.ResultsSeveral ligands showed notable interaction with at least two targets, but the strong interaction with all the targets is shown by very few ligands. The pharmacokinetics of the interacting ligands was also predicted. The interacting ligands have good drug-likeness and brain availability essential for drugs with intracranial targets.ConclusionThese results suggest that biaryl scaffold may be pliable to drug development for neuroprotection in AD and that the synthesis of further analogues to optimize these properties should be considered.Electronic supplementary materialThe online version of this article (10.1186/s12868-018-0472-6) contains supplementary material, which is available to authorized users.

Anti-allergic activities of Umbelliferone against histamine- and Picryl chloride-induced ear edema by targeting Nrf2/iNOS signaling in mice

“…The UMB physicochemical and pharmacokinetic analysis was determined using in silico approaches [ 39 , 40 ]. The UMB showed promising physicochemical properties such as logP, water-solubility, lipid solubility, and drug likeness behavior.…”

“…The ligand was prepared using Chemdraw_14.0 and saved as PDB format. The results were visualized using discovery studio visulaizer_16 and protein ligand interaction profiler online server [ 39 , 40 ].…”

“…The docking process of the UMB with the studied protein was validated and the root mean squared deviation (RMSD) was determined using LigRMSD software. The co-crystalized ligand was extracted and redocked with same protein and the RMSD value was calculated [ 39 , 40 ].…”

“…The pharmacokinetics analysis of the Umbelliferone was performed to determine the pharmacokinetic behavior of the UMB [ 39 , 40 ]. The Swiss target prediction software ( http://www.swissadme.ch/index.php ) was used to assess the ADME (absorption, distribution, metabolism and excretion), bioavailability, physicochemical characteristics, lipophilicity and drug likeness behavior was analyzed as reported previously [ 39 , 40 ].…”

Essential Oil of <em>Lippia origanoides</em> H.B.K.: A Promising Compound Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease

“…In the analysis, carvacrol had a higher docking score than the other structures used as ligands (Carvacrol > Thymol > p-cymene), showing ΔG of -6.64 with E20 and -5.70 with NAG, and the other molecules, values not too far apart. According to literature reports the binding energy of Donepezilla, an AD drug co-crystallized in the protein struc-ture, is around -11.0 [43,44]. Although the scores of phytoconstituents did not exceed the values of Donepezil, they show interactive potential with AchE.…”