Insights from molecular docking and molecular dynamics on the potential of vitexin as an antagonist candidate against lipopolysaccharide (LPS) for microglial activation in neuroinflammation

Abstract

Background Neuroinflammation has been identified to be the key player in most neurodegenerative diseases. If neuroinflammation is left to be unresolved, chronic neuroinflammation will be establish. Such situation is due to the overly-activated microglia which have the tendency to secrete an abundance amount of pro-inflammatory cytokines into the neuron microenvironment. The abundance of pro-inflammatory cytokines will later cause toxic and death to neurons. Toll-like receptor 4 (TLR4)/MD-2 complex found on the cell surface of microglia is responsible for the attachment of LPS and activation of nuclear factor-κB (NF-κB) downstream signalling pathway. Albeit vitexin has been shown to possess anti-inflammatory property, however, little is known on its ability to bind at the binding site of TLR4/MD-2 complex of microglia as well as to be an antagonist for LPS. Results The present study reveals that both vitexin and donepezil are able to bind at the close proximity of LPS binding site located at the TLR4/MD-2 complex with the binding energy of − 4.35 and − 9.14 kcal/mol, respectively. During molecular dynamic simulations, both vitexin and donepezil formed stable complex with TLR4/MD-2 throughout the 100 ns time length with the root mean square deviation (RMSD) values of 2.5 Å and 4.0 Å, respectively. The root mean square fluctuation (RMSF) reveals that both compounds are stable. Interestingly, the radius of gyration (rGyr) for donepezil shows notable fluctuations when compare with vitexin. The MM-GBSA results showed that vitexin has higher binding energy in comparison with donepezil. Conclusions Taken together, the findings suggest that vitexin is able to bind at the binding site of TLR4/MD-2 complex with more stability than donepezil throughout the course of 100 ns simulation. Hence, vitexin has the potential to be an antagonist candidate for LPS.

In Silico Approach in the Evaluation of Pro-Inflammatory Potential of Polycyclic Aromatic Hydrocarbons and Volatile Organic Compounds through Binding Affinity to the Human Toll-Like Receptor 4

“…TLR4/MD-2 complex found on the cell surface of target cells is responsible for the attachment of LPS and activation of NF-κB downstream signaling pathway. The best-docked scoring pose as determined by AutoDock Vina was selected and visualized by using BIOVIA Discovery Studio Visualizer [ 33 ].…”

“…Higher RMSF values are indicative of the high residue flexibility [ 38 ] while lower values correspond to more stable ligand binding [ 33 ]. The plotted values for the RMSF for Apo-TLR4 and TLR4-VOC complexes were generated via MATLAB R2021a.…”

Effect of tricyclic 1,2-thiazine derivatives in neuroinflammation induced by preincubation with lipopolysaccharide or coculturing with microglia-like cells

“…The binding affinity was found as − 9.2 kcal/mol for TP4 and − 8.9 kcal/mol for TP8. The reference value for Donepezil, a drug used in AD treatment [45,46], is reported as − 9.14 kcal/mol [47] (AutoDock scoring function, our studies − 9.1 kcal/mol, AutoDock Vina scoring function). It was reported that Leu54, Lys89, Arg90, Lys91, Lys122, Ile124, Lys125, Lys128, Tyr131 and Lys132 are the essential site for the LPS to bind for the microglia to be activated [43,44,47].…”

Anti-Inflammatory Mechanisms of Dietary Flavones: Tapping into Nature to Control Chronic Inflammation in Obesity and Cancer

“…Our own studies, screening protein libraries, revealed new unexpected mechanisms on how apigenin, through its direct interaction with an RNA binding protein, can regulate abnormal alternative splicing in cancer, results that lead to demonstrating how apigenin increases the efficacy of anti-cancer treatments [ 229 , 230 , 231 ]. The use of molecular dynamics has also provided valuable mechanistic insights into flavone interactions with proteins or DNA [ 232 , 233 , 234 , 235 ]. There are additional areas of unmet need that warrant further investigation including the development of food formulations that can deliver medically active doses and large epidemiological studies.…”