Novel ligand-based docking; molecular dynamic simulations; and absorption, distribution, metabolism, and excretion approach to analyzing potential acetylcholinesterase inhibitors for Alzheimer's disease

Vijayakumar, Sekar; Palani, M.; Prabhu, S.; Singh, Ram Avadhar Sanjeevkumar

doi:10.1016/j.jpha.2017.07.006

Cited by 58 publications

(31 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In previous works of Szwajgier [26,27], quercetin and kaempferol were efficient AChE and BChE inhibitors, whereas the activity of rutin was considerably lower in comparison to its aglycone [26,28]. Efficient inhibition of AChE, BChE, or both by quercetin [29,30] as well as rutin was also confirmed by other authors [29,31,32]. Additionally, other authors demonstrated anti-AChE activity of quercetin in vivo in the brain tissue of zebrafish in AD models [33,34].…”

Section: Discussionsupporting

confidence: 53%

Activity-guided isolation of cholinesterase inhibitors quercetin, rutin and kaempferol from Prunus persica fruit

Szwajgier

Borowiec

Zapp

2020

Zeitschrift Für Naturforschung C

View full text Add to dashboard Cite

Prunus persica fruit is a source of anti-cholinesterase agents and led to an increase of acetylcholine levels in brain tissue as a usefull tool in the Alzheimer’s disease therapy. This study aimed to propose a convenient method for the purification of cholinesterase inhibitors from P. persica water extract. Water extract from the fruit was ultrafiltered (0.2 μm→5 kDa→3 kDa) followed by preparative chromatography (Sephadex LH-20, high pressure C18) and high pressure analytical C18 chromatography. The chemical structures of inhibitors were confirmed using infrared and 1H-NMR spectroscopies. The anti-acetylcholinesterase activity was measured using the colorimetric method in fractions obtained after each stage of purification. Polyphenolic cholinesterase inhibitors identified in peach fruit were kaempferol, quercetin and quercetin-3-O-rhamnoglucoside (rutin). The relatively fast purification procedure elaborated in this work can be adopted for the isolation of phenolic cholinesterase inhibitors from fruit extracts related to P. persica fruit.

show abstract

Section: Discussionsupporting

confidence: 53%

Activity-guided isolation of cholinesterase inhibitors quercetin, rutin and kaempferol from Prunus persica fruit

Szwajgier

Borowiec

Zapp

2020

Zeitschrift Für Naturforschung C

View full text Add to dashboard Cite

show abstract

“…Molecular docking approach identifies suitable drug molecules for the target of interest (Roy et al., 2015 ; Sharma et al., 2011 ; Subhani et al., 2015 ; Vijayakumar et al., 2018 ). The docking result shows the potential of Dex to bind within the receptor pockets or active sites ( Figure 2 ) and the hydrogen bond interactions within specified distances ( Figures 3 and 4 ).…”

Section: Resultsmentioning

confidence: 99%

Computational insight of dexamethasone against potential targets of SARS-CoV-2

Fadaka

Sibuyi

Madiehe

et al. 2020

Journal of Biomolecular Structure and Dynamics

View full text Add to dashboard Cite

The health sector has been on the race to find a potent therapy for coronavirus disease (COVID)-19, a diseases caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2. Repurposed anti-viral drugs have played a huge role in combating the virus, and most recently, dexamethasone (Dex) have shown its therapeutic activity in severe cases of COVID-19 patients. The study sought to provide insights on the anti-COVID-19 mechanism of Dex at both atomic and molecular level against SARS-CoV-2 targets. Computational methods were employed to predict the binding affinity of Dex to SARS-CoV-2 using the Schrodinger suite (v2020-2). The target molecules and ligand (Dex) were retrieved from PDB and PubChem, respectively. The selected targets were SARS-CoV-2 main protease (Mpro), and host secreted molecules glucocorticoid receptor, and Interleukin-6 (IL-6). Critical analyses such as Protein and ligand preparation, molecular docking, molecular dynamic (MD) simulations, and absorption, distribution, metabolism, excretion (ADME), and toxicity analyses were performed using the targets and the ligand as inputs. Dex showed stronger affinity to its theoretical (glucocorticoid) receptor with a superior docking score of À14.7 and a good binding energy value of À147.48 kcal/mol; while short hydrogen bond distances were observed in both Mpro and IL-6 when compared to glucocorticoid receptor. Based on these findings, Dex-target complexes were used to perform MD simulations to analyze Dex stability at 50 ns. This study demonstrates that Dex could bind to both the viral and host receptors as a potential drug candidate for COVID-19. To ascertain the biological fitness of this study, other SARS-CoV-2 targets should be explored. Also, the in vitro studies of dexamethasone against several SARS-CoV-2 targets warrant further investigation.

show abstract

“…Counter ions were added to the complex to neutralize the solvated system. The complex energy was minimized using an OPLS3e force field [ 26 , 27 ]. In the current study, isothermal-isobaric (NPT) ensemble was employed.…”

Section: Methodsmentioning

confidence: 99%

Structure-based virtual screening, in silico docking, ADME properties prediction and molecular dynamics studies for the identification of potential inhibitors against SARS-CoV-2 Mpro

Anbuselvam¹,

Rendine

Mohammed³

et al. 2021

Mol Divers

View full text Add to dashboard Cite

COVID-19 is a viral pandemic caused by SARS-CoV-2. Due to its highly contagious nature, millions of people are getting affected worldwide knocking down the delicate global socio-economic equilibrium. According to the World Health Organization, COVID-19 has affected over 186 million people with a mortality of around 4 million as of July 09, 2021. Currently, there are few therapeutic options available for COVID-19 control. The rapid mutations in SARS-CoV-2 genome and development of new virulent strains with increased infection and mortality among COVID-19 patients, there is a great need to discover more potential drugs for SARS-CoV-2 on a priority basis. One of the key viral enzymes responsible for the replication and maturation of SARS-CoV-2 is M pro protein. In the current study, structure-based virtual screening was used to identify four potential ligands against SARS-CoV-2 M pro from a set of 8,722 ASINEX library compounds. These four compounds were evaluated using ADME filter to check their ADME profile and druggability, and all the four compounds were found to be within the current pharmacological acceptable range. They were individually docked to SARS-CoV-2 M pro protein to assess their molecular interactions. Further, molecular dynamics (MD) simulations was carried out on protein–ligand complex using Desmond at 100 ns to explore their binding conformational stability. Based on RMSD, RMSF and hydrogen bond interactions, it was found that the stability of protein–ligand complex was maintained throughout the entire 100 ns simulations for all the four compounds. Some of the key ligand amino acid residues participated in stabilizing the protein–ligand interactions includes GLN 189, SER 10, GLU 166, ASN 142 with PHE 66 and TRP 132 of SARS-CoV-2 M pro . Further optimization of these compounds could lead to promising drug candidates for SARS-CoV-2 M pro target.

show abstract

Novel ligand-based docking; molecular dynamic simulations; and absorption, distribution, metabolism, and excretion approach to analyzing potential acetylcholinesterase inhibitors for Alzheimer's disease

Cited by 58 publications

References 30 publications

Activity-guided isolation of cholinesterase inhibitors quercetin, rutin and kaempferol from Prunus persica fruit

Activity-guided isolation of cholinesterase inhibitors quercetin, rutin and kaempferol from Prunus persica fruit

Computational insight of dexamethasone against potential targets of SARS-CoV-2

Structure-based virtual screening, in silico docking, ADME properties prediction and molecular dynamics studies for the identification of potential inhibitors against SARS-CoV-2 Mpro

Contact Info

Product

Resources

About