In Silico Pharmacogenetics CYP2D6 Study Focused on the Pharmacovigilance of Herbal Antidepressants

Don, Charleen G.; Smieško, Martin

doi:10.3389/fphar.2020.00683

Front. Pharmacol.

2020

DOI: 10.3389/fphar.2020.00683

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In Silico Pharmacogenetics CYP2D6 Study Focused on the Pharmacovigilance of Herbal Antidepressants

Charleen G. Don

Martin Smieško

Abstract: The annual increase in depression worldwide together with an upward trend in the use of alternative medicine as treatment asks for developing reliable safety profiles of herbal based medicine. A considerable risk on adverse reactions exists when herbal remedies are combined with prescription medication. Around 25% of the drugs, including many antidepressants, depend on the activity of CYP2D6 for their metabolism and corresponding efficacy. Therefore, probing CYP2D6 inhibition by the active substances in herbal… Show more

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Cited by 3 publications

References 67 publications

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Computational Analysis of Phase I Metabolism in Clinically Studied Flavoalkaloids: Molecular Docking, MMGBSA Binding Energy Calculations, and Molecular Dynamics Simulations

Kallurkar,

Thakur,

Jadhav

et al. 2024

ChemistrySelect

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Flavoalkaloids, a potent class of cyclin‐dependent kinase inhibitors, have undergone extensive clinical trials across various cancer types. Among them, flavopiridol, riviciclib, and voruciclib are the most advanced candidates. These molecules are lipophilic and possess functional groups conducive to both phase I and phase II metabolism in the liver. This study employs in‐silico methods to identify the potential cytochrome P450‐mediated sites of phase I metabolism (SOM) in these compounds. According to two web‐server‐based predictions, the N‐methyl group was identified as the primary SOM in these compounds, showing the highest probability score for involvement of CYP3A4. Docking studies conducted using both Glide and the induced‐fit method further confirmed N‐demethylation as a significant metabolic pathway predominantly catalyzed by CYP3A4. The distance between the N‐methyl group of the docked ligands and the iron atom of the heme ranged from 3 to 7 Å, with flavopiridol's N‐methyl group positioned closest to the heme iron at 3.16 Å. The 100 ns molecular dynamic simulations additionally validated the stability of the interaction between flavoalkaloids and the heme Fe. Similarly, the docking‐based SOM predictions matched the experimental SOM for other approved drugs. Thus, employing docking‐based SOM predictions holds potential for enhancing lead optimization efforts in future medicinal chemistry research.

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Computational Analysis of Phase I Metabolism in Clinically Studied Flavoalkaloids: Molecular Docking, MMGBSA Binding Energy Calculations, and Molecular Dynamics Simulations

Kallurkar,

Thakur,

Jadhav

et al. 2024

ChemistrySelect

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In vitro, in vivo, and in silico approaches for evaluating the preclinical DMPK profiles of ammoxetine, a novel chiral serotonin and norepinephrine reuptake inhibitor

Zhu,

Li,

Luo

et al. 2024

Front. Pharmacol.

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Background and AimAmmoxetine, a novel chiral serotonin and norepinephrine reuptake inhibitor, holds promise for major depressive disorder treatment. This study aimed to thoroughly investigate its preclinical drug metabolism and pharmacokinetics (DMPK) profiles.MethodsThe preclinical DMPK profiles of ammoxetine were examined through in vitro, in vivo, and in silico methods.ResultsAssessment of blood-brain barrier penetration via MDCK-MDR1 cells revealed strong brain permeation by ammoxetine, despite being a probable P-glycoprotein (P-gp) substrate. Molecular docking indicated a robust binding interaction between ammoxetine and P-gp. Ammoxetine was well absorbed orally, with Tmax ranging from 0.75 to 3.83 h in rats and 0.75–1.40 h in beagle dogs. At a 2 mg/kg dose in beagle dogs, ammoxetine exhibited an absolute bioavailability of approximately 42%. Plasma protein binding rates were around 50%–60% in beagle dogs, rats, and humans, suggesting moderate binding. Tissue distribution studies displayed rapid and extensive ammoxetine spread in major rat tissues post-gavage, with notable brain exposure and no tissue accumulation. Cumulative excretion rates in rats’ urine, feces, and bile accounted for only 1.11% of the total administered drug, indicating extensive transformation into metabolites. Chiral inversion of ammoxetine was absent in vivo. Metabolic stability varied across species using liver microsomes, but beagle dogs showed clearance rates more akin to humans. Metabolic pathways unveiled two key metabolites, M1 and M2. M1, likely generated through methylenedioxyphenyl ring oxidation, involves CYP2C19 and CYP3A4, crucial human cytochrome P450 (CYP) enzymes for liver metabolism, while M2 is M1’s glucuronide conjugate. Ammoxetine may exhibit saturation elimination trends with increasing doses in rats and beagle dogs. A high-throughput assay using the cocktail-substrate method indicated weak CYP inhibition by ammoxetine on CYP2D6 and CYP1A2, with minimal effects on other CYP enzymes, suggesting a low likelihood of CYP inhibition-related drug-drug interactions.ConclusionThis study presents encouraging DMPK profiles of ammoxetine, backing its potential as a candidate compound for future clinical assessments.

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In Silico ADME Profiling of Salubrinal and Its Analogues

Zadorozhnii

Kiselev

Харченко

2022

Future Pharmacology

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This work reports on a complex in silico assessment of the ADME properties of Salubrinal (S1) and 54 of its structural analogues containing a cinnamic acid residue (S2–S40) or a quinoline ring (S41–S55). In the work for (Q)SAR forecast, the online servers SwissADME, ADMETlab, admetSAR 2.0, Molinspiration, ALOGPS 2.1, pkCSM, SuperCYPsPred, and Vienna LiverTox were used. In addition, using AutoDock Vina, molecular docking studies were performed with transporter proteins and metabolic enzymes, which were intended to interact with the test compounds. In silico assessment of the ability of the S1–S55 compounds to be absorbed in the intestine was carried out using the SAR classification models implemented in these servers, as well as on the basis of two empirical rules—Lipinski’s and Veber’s. Most of the studied compounds had moderate lipophilicity (MLogP ˂ 4.15) and a polar surface area of less than 140 Å2. They complied with Lipinski’s and Veber’s rules, and are predicted to have good intestinal absorption. In silico analysis of the distribution of the S1–S55 compounds throughout the body, the volume of distribution at steady-state (Vdss), the ability to bind to blood plasma proteins and cross the blood-brain barrier (BBB) were taken into account. Most compounds are predicted to have low or medium Vdss and the ability to cross the BBB. Molecular docking studies were carried out with the structures most important for drug binding of blood plasma proteins, human serum albumin (HSA), and alpha-1-acid glycoprotein (AGP). The studies showed that these substances can effectively bind to blood plasma proteins. When assessing metabolism, the prediction of inhibitory and substrate activity to cytochromes P450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) was carried out. For most of these enzymes, the analyzed compounds are likely to be potential inhibitors, as indicated by the molecular docking data. For all studied compounds, a low total clearance (CLtot. ˂ 5 mL/min/kg) and a half-life time (T1/2 ˂ 3 h) are predicted.

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In Silico Pharmacogenetics CYP2D6 Study Focused on the Pharmacovigilance of Herbal Antidepressants

Cited by 3 publications

References 67 publications

Computational Analysis of Phase I Metabolism in Clinically Studied Flavoalkaloids: Molecular Docking, MMGBSA Binding Energy Calculations, and Molecular Dynamics Simulations

Computational Analysis of Phase I Metabolism in Clinically Studied Flavoalkaloids: Molecular Docking, MMGBSA Binding Energy Calculations, and Molecular Dynamics Simulations

In vitro, in vivo, and in silico approaches for evaluating the preclinical DMPK profiles of ammoxetine, a novel chiral serotonin and norepinephrine reuptake inhibitor

In Silico ADME Profiling of Salubrinal and Its Analogues

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