Comparison and summary of in silico prediction tools for CYP450-mediated drug metabolism

Zhai, Jingchen; Man, Viet Hoang; Ji, Beihong; Cai, Lianjin; Wang, Junmei

doi:10.1016/j.drudis.2023.103728

Cited by 6 publications

(5 citation statements)

References 56 publications

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“…Among them, we focused on the metabolism of xenobiotics by cytochrome P450, drug metabolism-cytochrome P450 and Toll and IMD signaling pathway. The metabolism of xenobiotics by cytochrome P450, and drug metabolism-cytochrome P450 were upregulated to varying degrees and responsible for the metabolic breakdown of drugs/xenobiotics via particular enzyme systems (e.g., the CYP450 family) 29 . Cytochromes P450 enzymes primarily function as oxidizing agents, with specific P450 families playing a pivotal role in drug metabolism 30 .…”

Section: Resultsmentioning

confidence: 99%

Fitness effects of synthetic and natural diet preservatives on the edible insect Bombyx mori

Lei,

Qian,

Zhu

et al. 2024

npj Sci Food

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Silkworm pupae as widely consumed insect products are good biosources of protein and micronutrients. Silkworm rearing throughout the year can be achieved by feeding them an artificial diet instead of native plants, facilitating extensive pupa production. However, artificial diets are prone to spoilage caused by bacterial contamination. Here, we evaluated the antiseptic effect of ethylparaben (EP, chemical preservative) and medium-chain fatty acids (MCFA, natural preservative) in a silkworm artificial diet. Results showed that both preservatives effectively inhibited pathogenic bacterial growth. Furthermore, the addition of EP or MCFA did not negatively impact the production capacity of silkworms and the homeostasis of gut microbiota. However, the expression of genes involved in detoxification such as Ugt2, and immune response such as Cecropin B, were upregulated after EP consumption. Therefore, natural preservative MCFA emerges as a suitable option from a safety perspective. These findings highlight future directions for improving insect artificial diet formulation.

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Section: Resultsmentioning

confidence: 99%

Fitness effects of synthetic and natural diet preservatives on the edible insect Bombyx mori

Lei,

Qian,

Zhu

et al. 2024

npj Sci Food

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“…Consequently, inhibiting CYP2D6 may raise the potential for toxicity. Hence, in this research, compounds that do not hinder the CYP2D6 enzyme were selected [46]. According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS), there are six acute toxicity classes.…”

Section: Molecular Dockingmentioning

confidence: 99%

Exploration of the Active Compounds of Moringa Oleifera Lam as Hiv-1 Reverse Transcriptase Inhibitor: A Network Pharmacology and Molecular Docking Approach

FITRIANA,

MUN’IM,

FIRDAYANI

et al. 2024

Int J App Pharm

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Objective: This study aims to predict the active compound of Moringa oleifera for the treatment of Human Immunodeficiency Virus (HIV), specifically targeting the HIV-1 reverse transcriptase (HIV-1 RT) enzyme using network pharmacology and molecular docking approach. Methods: The active ingredients of M. oleifera, were screened from the Knapsack database. Subsequently, HIV-1 RT and its related target compounds were retrieved from the Genecard database. The analysis of common targets involved protein-protein interactions (PPI) analysis using string databases and constructing interaction IDs using Cytoscape software. Gene Ontology (GO) functional and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Molecular docking studies were conducted using AutoDock Vina software to validate the results of the network pharmacological analysis. Results: A total of 63 active ingredients and 8601 targets related to HIV-1 RT were identified. The network analysis, encompassing GO and KEGG enrichment, revealed strong associations of common targets with key signaling pathways such as Tumor Necrosis Factor (TNF), Toll Like Receptor (TLR), and apoptosis. Additionally, 11 compounds of M. oleifera including apigenin, benzyl isothiocyanate, benzylamine, caffeic acid, ferulic acid, epicatechin, kaempferol, gallic acid, luteolin, syringic acid and vanillin were identified as potential vital compounds. Molecular docking analysis highlighted apigenin and kaempferol as the most promising compounds, exhibiting the lowest binding affinity to the HIV-1 RT enzyme. These compounds correlated with caspase-3(CASP3), caspase-9 (CASP9), and BCL2 Apoptosis Regulator (BAX) protein, stimulating cell apoptosis through multiple pathways. Conclusion: The study highlighted that apigenin and kaempferol are potential compound of M. oleifera in HIV-1 treatment through inhibition activity at HIV-1 RT Enzyme.

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“…In contrast, structure-based methods directly use the three-dimensional structures of CYP enzymes. “Machine learning”， which has typically been used to support ligand-based modeling [ 9 , 10 ], has the capacity to simultaneously incorporate aspects associated with ligand-based and structure-based approaches within a single model [ 11 ], and therefore may be considered a third category. The success of ligand-based modeling is impressive, with the caveat that a limitation or bias is necessarily imposed by the training set.…”

Section: Introductionmentioning

confidence: 99%

Water Exchange from the Buried Binding Sites of Cytochrome P450 Enzymes 1A2, 2D6, and 3A4 Correlates with Conformational Fluctuations

Guvench

2024

Molecules

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Human cytochrome P450 enzymes (CYPs) are critical for the metabolism of small-molecule pharmaceuticals (drugs). As such, the prediction of drug metabolism by and drug inhibition of CYP activity is an important component of the drug discovery and design process. Relative to the availability of a wide range of experimental atomic-resolution CYP structures, the development of structure-based CYP activity models has been limited. To better characterize the role of CYP conformational fluctuations in CYP activity, we perform multiple microsecond-scale all-atom explicit-solvent molecular dynamics (MD) simulations on three CYP isoforms, 1A2, 2D6, and 3A4, which together account for the majority of CYP-mediated drug metabolism. The MD simulations employ a variety of positional restraints, ranging from keeping all CYP atoms close to their experimentally determined coordinates to allowing full flexibility. We find that, with full flexibility, large fluctuations in the CYP binding sites correlate with efficient water exchange from these buried binding sites. This is especially true for 1A2, which, when restrained to its crystallographic conformation, is unable to exchange water between the binding site and bulk solvent. These findings imply that, in addition to crystal structures, a representative ensemble of conformational states ought to be included when developing structure-based CYP activity models.

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Comparison and summary of in silico prediction tools for CYP450-mediated drug metabolism

Cited by 6 publications

References 56 publications

Fitness effects of synthetic and natural diet preservatives on the edible insect Bombyx mori

Fitness effects of synthetic and natural diet preservatives on the edible insect Bombyx mori

Exploration of the Active Compounds of Moringa Oleifera Lam as Hiv-1 Reverse Transcriptase Inhibitor: A Network Pharmacology and Molecular Docking Approach

Water Exchange from the Buried Binding Sites of Cytochrome P450 Enzymes 1A2, 2D6, and 3A4 Correlates with Conformational Fluctuations

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