Discovery of natural 15-LOX small molecule inhibitors from Chinese herbal medicine using virtual Screening, biological evaluation and molecular dynamics studies

Li, Yatong; Zhang, Yuxin; Wu, Xia; Gao, Yanbin; Guo, Jiansheng; Tian, Yulang; Lin, Ziyue; Wang, Xing

doi:10.1016/j.bioorg.2021.105197

Cited by 11 publications

(4 citation statements)

References 50 publications

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“…Binding energy (ΔG bind ) is the binding energy between the protein pocket and the ligand. It was calculated by the Molecular Mechanic/Poisson-Boltzmann Surface Area (MM/PBSA) method and according to the following equation: ΔG bind = G complex −(G protein + G ligand ) ≈ ΔE vdw + ΔE ele + ΔG sol where E vdw and E ele are the van der Waals and electrostatic energy and G sol is the total solvation free energy ( Miller et al, 2012 ; Li et al, 2021 ). The RMSD, RMSF values, and energy contribution for individual residues were imported into GraphPad Prism version 8.4.0 software to make the graph, respectively.…”

Section: Methodsmentioning

confidence: 99%

Discovery of METTL3 Small Molecule Inhibitors by Virtual Screening of Natural Products

Yuan

et al. 2022

Front. Pharmacol.

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N6-Methyladenosine (m6A) is the most prevalent mRNA modification in mammalian cells that is mainly catalyzed by the methyltransferase complex of methyltransferase-like 3 and methyltransferase-like 14 (METTL3-METTL14). Many lines of evidence suggest that METTL3 plays important roles in several diseases such as cancers and viral infection. In the present study, 1,042 natural products from commercially available sources were chosen to establish a screening library, and docking-based high-throughput screening was performed to discover potential METTL3 inhibitors. The selected compounds were then further validated by an in vitro methyltransferase inhibition assay in which m6A content was determined by LC-MS/MS. A cellular assay of the inhibition of m6A methylation was performed to determine the METTL3 inhibitory activity of the selected compound. CCK-8 assay was applied to evaluate the effects of the selected compound on tumor cell viability. Additionally, binding mode analysis, molecular dynamics (MD) simulation, and binding free energy analysis were performed to study the process and characteristics of inhibitor binding. Finally, quercetin was identified as a METTL3 inhibitor with an IC50 value of 2.73 μM. The cellular assay of m6A methylation inhibition showed that quercetin decreased m6A level in a dose-dependent manner in MIA PaCa-2 pancreatic cancer cells. CCK-8 assay showed quercetin efficiently inhibited the proliferation of MIA PaCa-2 and Huh7 tumor cells, with IC50 values 73.51 ± 11.22 μM and 99.97 ± 7.03 μM, respectively. Molecular docking studies revealed that quercetin filled the pocket of the adenosine moiety of SAM but not the pocket of the SAM methionine in the METTL3 protein, and hydrogen bonds, hydrophobic interactions, and pi-stacking were formed. The values of the root mean square deviation (RMSD), the root mean square fluctuations (RMSF), and binding free energy suggested that quercetin can efficiently bind to the pocket of the METTL3 protein and form a stable protein-ligand complex. The present study is the first to identify METTL3 inhibitors from natural products, thus providing a basis for subsequent research and facilitating the development of METTL3-targeting drugs for diseases.

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Section: Methodsmentioning

confidence: 99%

Discovery of METTL3 Small Molecule Inhibitors by Virtual Screening of Natural Products

Yuan

et al. 2022

Front. Pharmacol.

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“…To test the reliability and accuracy of the docking program, 3ZD was extracted from the co-crystal structure and re-docked into the binding pocket of thrombin using the surflex-docking program preset. The root mean square deviation (RMSD) was used to quantify the difference between the co-crystallized and docked conformations of all heavy atoms in 3ZD according to the following formula [37]: d denotes the distance among N pairs of equivalent atoms excluding hydrogen atoms. A lower value of RMSD suggested a higher degree of similarity between the co-crystal and docked conformation of 3ZD.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…A simulation system was constructed using a mixture of thrombin protein, panaxatriol or argatroban, ions and water, based on the molecular dynamics simulation-related literature [37,39]. The initial atomic coordinates of the thrombin-inhibitor complex for MD simulation were obtained using the Surflex-Dock approach.…”

Section: Molecular Dynamics and Binding Free Energy Calculationmentioning

confidence: 99%

“…The free energy of binding for thrombin and panaxatriol or argatroban was measured with molecular mechanics energies and methods such as generalized born and surface area continuum solvation [37]. The total free energy of binding was also broken down into contributions from each residue to determine the most important residues in the binding of thrombin to the two ligands using MM/GBSA decomposition method [45].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Discovery and characterization of panaxatriol as a novel thrombin inhibitor from Panax notoginseng using combination of computational and experimental approach

Wang,

Ma,

Zuo

et al. 2024

Planta Med

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Thrombin is a crucial enzyme in the coagulation cascade, and inhibitors of thrombin have been extensively studied as potential antithrombotic agents. The objective of this study was to identify natural inhibitors of thrombin from Panax notoginseng and evaluate their biological activity in vitro and binding characteristics. A combined approach involving molecular docking, thrombin inhibition assay, surface plasmon resonance (SPR) and molecular dynamics simulation was utilized to identify natural thrombin inhibitors. The results demonstrated that that panaxatriol directly inhibits thrombin with an IC50 of 10.3 μM. Binding studies using SPR revealed that panaxatriol interacts with thrombin with a KD value of 7.8 μM. Molecular dynamics analysis indicated that the thrombin-panaxatriol system reached equilibrium rapidly with minimal fluctuations, and the calculated binding free energy was -23.8 kcal/mol. The interaction between panaxatriol and thrombin involves the amino acid residues Glu146, Glu192, Gly216, Gly219, Tyr60A, and Trp60D. This interaction provides a mechanistic basis for further optimizing panaxatriol as a thrombin inhibitor. Our study has shown that panaxatriol serves as a direct thrombin inhibitor, laying the groundwork for further research and development of novel thrombin inhibitor.

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Molecular Docking for Virtual Screening of Potential Active Ingredients in Chinese Medicines

Xie,

Wang

2024

Quality Control of Chinese Medicines

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Discovery of natural 15-LOX small molecule inhibitors from Chinese herbal medicine using virtual Screening, biological evaluation and molecular dynamics studies

Cited by 11 publications

References 50 publications

Discovery of METTL3 Small Molecule Inhibitors by Virtual Screening of Natural Products

Discovery of METTL3 Small Molecule Inhibitors by Virtual Screening of Natural Products

Discovery and characterization of panaxatriol as a novel thrombin inhibitor from Panax notoginseng using combination of computational and experimental approach

Molecular Docking for Virtual Screening of Potential Active Ingredients in Chinese Medicines

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