Identification of Gly/NMDAR Antagonist from <i>Chromolaena odorata’s</i> Derived Phytoconstituents using Induced Fit Docking Approach

Ti, David; Oi, Omotuyi; Od, Agboola; Dc, Okonkwo; Adelakun, Niyi Samuel

doi:10.1101/610006

Cited by 4 publications

(4 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ugale and Bari reported that amino acid residues Arg131, Pro124, and Thr126 are essential for inhibiting the Gly/NMDA receptor [70,71]. These interactions were also noticed by Devid et al [72] with some additional interactions (GLN13, ASP224, and Trp223 residues). Our results are in correspondence with these previous reports.…”

Section: Nmda-complexmentioning

confidence: 52%

Multitargeted Virtual Screening and Molecular Simulation of Natural Product-like Compounds against GSK3β, NMDA-Receptor, and BACE-1 for the Management of Alzheimer’s Disease

et al. 2023

View full text Add to dashboard Cite

The complexity of Alzheimer’s disease (AD) and several side effects of currently available medication inclined us to search for a novel natural cure by targeting multiple key regulatory proteins. We initially virtually screened the natural product-like compounds against GSK3β, NMDA receptor, and BACE-1 and thereafter validated the best hit through molecular dynamics simulation (MDS). The results demonstrated that out of 2029 compounds, only 51 compounds exhibited better binding interactions than native ligands, with all three protein targets (NMDA, GSK3β, and BACE) considered multitarget inhibitors. Among them, F1094-0201 is the most potent inhibitor against multiple targets with binding energy −11.7, −10.6, and −12 kcal/mol, respectively. ADME-T analysis results showed that F1094-0201 was found to be suitable for CNS drug-likeness in addition to their other drug-likeness properties. The MDS results of RMSD, RMSF, Rg, SASA, SSE and residue interactions indicated the formation of a strong and stable association in the complex of ligands (F1094-0201) and proteins. These findings confirm the F1094-0201’s ability to remain inside target proteins’ binding pockets while forming a stable complex of protein-ligand. The free energies (MM/GBSA) of BACE-F1094-0201, GSK3β-F1094-0201, and NMDA-F1094-0201 complex formation were −73.78 ± 4.31 kcal mol−1, −72.77 ± 3.43 kcal mol−1, and −52.51 ± 2.85 kcal mol−1, respectively. Amongst the target proteins, F1094-0201 have a more stable association with BACE, followed by NMDA and GSK3β. These attributes of F1094-0201 indicate it as a possible option for the management of pathophysiological pathways associated with AD.

show abstract

Section: Nmda-complexmentioning

confidence: 52%

Multitargeted Virtual Screening and Molecular Simulation of Natural Product-like Compounds against GSK3β, NMDA-Receptor, and BACE-1 for the Management of Alzheimer’s Disease

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Moreover, many studies have previously reported that certain phytochemicals have neuroprotective properties such as protocatechuic acid [90,91], syringic acid [91,92], vanillic acid [93], gallic acid [91], 4-hydroxybenzoic acid [94], chlorogenic acid [91], luteolin [95], quercetin [95], taxifolin [96], quercetin-3-O-rutinoside (rutin) [95], and isoorientin [97]. Furthermore, in silico studies have predicted that certain plant phytochemicals have NMDAR antagonist activity and could prevent L-Glu excitotoxicity, such as chlorogenic acid [98], quercetin, gallic acid, protocatechuic acid, and vanillic acid [99], and the LC-MS results from this study confirm that acai berry extracts contain these phytochemicals (Table 1). This implies that acai berry extracts may retain a range of phytochemicals that have antioxidant and anti-excitotoxicity effects that could be neuroprotective and reduce vulnerability to excessive L-Glu levels such as those associated with NDDs and stroke.…”

Section: Discussionmentioning

confidence: 99%

Acai Berry (Euterpe sp.) Extracts Are Neuroprotective against L-Glutamate-Induced Toxicity by Limiting Mitochondrial Dysfunction and Cellular Redox Stress

ALNasser

AlSaadi

Whitby

et al. 2023

Life

View full text Add to dashboard Cite

Aberrant accumulation of the neurotransmitter L-glutamate (L-Glu) has been implicated as a mechanism of neurodegeneration, and the release of L-Glu after stroke onset leads to a toxicity cascade that results in neuronal death. The acai berry (Euterpe oleracea) is a potential dietary nutraceutical. The aim of this research was to investigate the neuroprotective effects of acai berry aqueous and ethanolic extracts to reduce the neurotoxicity to neuronal cells triggered by L-Glu application. L-Glu and acai berry effects on cell viability were quantified using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays, and effects on cellular bioenergetics were assessed via quantitation of the levels of cellular ATP, mitochondrial membrane potential (MMP), and production of reactive oxygen species (ROS) in neuroblastoma cells. Cell viability was also evaluated in human cortical neuronal progenitor cell culture after L-Glu or/and acai berry application. In isolated cells, activated currents using patch-clamping were employed to determine whether L-Glu neurotoxicity was mediated by ionotropic L-Glu-receptors (iGluRs). L-Glu caused a significant reduction in cell viability, ATP, and MMP levels and increased ROS production. The co-application of both acai berry extracts with L-Glu provided neuroprotection against L-Glu with sustained cell viability, decreased LDH production, restored ATP and MMP levels, and reduced ROS levels. Whole-cell patch-clamp recordings showed that L-Glu toxicity is not mediated by the activation of iGluRs in neuroblastoma cells. Fractionation and analysis of acai berry extracts with liquid chromatography-mass spectrometry identified several phytochemical antioxidants that may have provided neuroprotective effects. In summary, the acai berry contains nutraceuticals with antioxidant activity that may be a beneficial dietary component to limit pathological deficits triggered by excessive L-Glu accumulations.

show abstract

“…The amino acid residues PRO124, THR126, and ARG131 are crucial for blocking the Gly/NMDA receptor, according to Ugale and Bari [25,70]. With some additional interactions (GLN13, TRP223, and ASP224), Devid et al [71] also noted these interactions. Our findings are consistent with these earlier publications.…”

Section: Molecular Interaction Analysis Of N-methyl-d-aspartate Recep...mentioning

confidence: 99%

Pharmacophore-Based Screening, Molecular Docking, and Dynamic Simulation of Fungal Metabolites as Inhibitors of Multi-Targets in Neurodegenerative Disorders

Iqbal,

Alsaweed,

Jamal

et al. 2023

Biomolecules

View full text Add to dashboard Cite

Neurodegenerative disorders, such as Alzheimer’s disease (AD), negatively affect the economic and psychological system. For AD, there is still a lack of disease-altering treatments and promising cures due to its complex pathophysiology. In this study, we computationally screened the natural database of fungal metabolites against three known therapeutic target proteins of AD. Initially, a pharmacophore-based, drug-likeness category was employed for screening, and it filtered the 14 (A–N) best hits out of 17,544 fungal metabolites. The 14 best hits were docked individually against GSK-3β, the NMDA receptor, and BACE-1 to investigate the potential of finding a multitarget inhibitor. We found that compounds B, F, and L were immuno-toxic, whereas E, H, I, and J had a higher LD50 dose (5000 mg/kg). Among the examined metabolites, the Bisacremine-C (compound I) was found to be the most active molecule against GSK-3β (ΔG: −8.7 ± 0.2 Kcal/mol, Ki: 2.4 × 106 M−1), NMDA (ΔG: −9.5 ± 0.1 Kcal/mol, Ki: 9.2 × 106 M−1), and BACE-1 (ΔG: −9.1 ± 0.2 Kcal/mol, Ki: 4.7 × 106 M−1). It showed a 25-fold higher affinity with GSK-3β, 6.3-fold higher affinity with NMDA, and 9.04-fold higher affinity with BACE-1 than their native ligands, respectively. Molecular dynamic simulation parameters, such as RMSD, RMSF, Rg, and SASA, all confirmed that the overall structures of the targeted enzymes did not change significantly after binding with Bisacremine-C, and the ligand remained inside the binding cavity in a stable conformation for most of the simulation time. The most significant hydrophobic contacts for the GSK-3β-Bisacremine-C complex are with ILE62, VAL70, ALA83, and LEU188, whereas GLN185 is significant for H-bonds. In terms of hydrophobic contacts, TYR184 and PHE246 are the most important, while SER180 is vital for H-bonds in NMDA-Bisacremine-C. THR232 is the most crucial for H-bonds in BACE-1-Bisacremine-C and ILE110-produced hydrophobic contacts. This study laid a foundation for further experimental validation and clinical trials regarding the biopotency of Bisacremine-C.

show abstract

Identification of Gly/NMDAR Antagonist from Chromolaena odorata’s Derived Phytoconstituents using Induced Fit Docking Approach

Cited by 4 publications

References 15 publications

Multitargeted Virtual Screening and Molecular Simulation of Natural Product-like Compounds against GSK3β, NMDA-Receptor, and BACE-1 for the Management of Alzheimer’s Disease

Multitargeted Virtual Screening and Molecular Simulation of Natural Product-like Compounds against GSK3β, NMDA-Receptor, and BACE-1 for the Management of Alzheimer’s Disease

Acai Berry (Euterpe sp.) Extracts Are Neuroprotective against L-Glutamate-Induced Toxicity by Limiting Mitochondrial Dysfunction and Cellular Redox Stress

Pharmacophore-Based Screening, Molecular Docking, and Dynamic Simulation of Fungal Metabolites as Inhibitors of Multi-Targets in Neurodegenerative Disorders

Contact Info

Product

Resources

About