CYP-450 Mediated Herb-Drug Interactions of Ashwagandha and AYUSH-64 Used in COVID-19 Integrative Management: A Case Example of Remdesivir

Abstract AimWithania somnifera Dunal (WS), known as Ashwagandha and AYUSH-64, a polyherbal formulation are repurposed for the management of COVID-19. The extensive use of these botanicals as home remedy along with other drugs for managing multifarious disease conditions is increasing over nations. This raises high chances of herb-drug interactions (HDIs) which may be beneficial, harmful, or even fatal. Therefore, current study aimed to explore the CYP mediated herb-drug interactions (HDIs) of Ashwagandha and AYUSH-64 along with case example of remdesivir to harness the best of these HDIs for integrative management of COVID-19Materials and MethodsThe aqueous extract of Ashwagandha and AYUSH-64 were characterized by LC-MS/MS. The in-silico pharmacokinetic (ADME) parameters were studied by using ADME tool. The in-vitro CYP-450 (CYP3A4, 2C8, 2D6) inhibition studies of WS and AYUSH-64 alone and in combination with a remdesivir were carried out resembling clinically scenario.ResultsTotal of 11 and 24 phytoconstituents were identified from the aqueous extract of Aswagandha and AYUSH-64. The in-silico ADME studies revealed that most of the phytoconstituents showed good oral bioavailability, drug likeliness, GI affinity and some of them displayed CYP-450 inhibitory activity. The in-vitro CYP-450 studies of remdesivir showed moderate inhibitory effect on CYP3A4, 2C8, 2D6. The aqueous extract of Aswagandha did not show any inhibitory activity towards all the studied CYP’s alone and in combination with remdesivir (IC50 >100µg/ml). Whereas, AYUSH-64 also followed the same trend but showed moderate inhibitory effect on CYP2C8 (IC50 <100µg/ml).ConclusionAswagandha did not exhibit HDIs with the CYP3A4, CYP2C8 and CYP2D6 thereby seem to be safe to co-administer with respective substrates. Whereas, AYUSH-64 only showed moderate HDIs towards CYP2C8 substrate among studied CYP enzymes. Caution is therefore warranted for prescribing AYUSH 64 along with CYP2C8 substrate drugs.

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Palladium(ii) complexes bearing 1-iminothiolate-3,5-dimethylpyrazoles: synthesis, cytotoxicity, DNA binding and enzymatic inhibition studies

New Journal of Chemistry ◽

10.1039/d0nj02825h ◽

2020 ◽

Vol 44 (45) ◽

pp. 19891-19901

Author(s):

Thales Reggiani de Moura ◽

Renan Diego Zanetti ◽

Debora Eduarda Soares Silva ◽

Renan Lira de Farias ◽

Antonio Eduardo Mauro ◽

...

Keyword(s):

Dna Binding ◽

Inhibitory Activity ◽

In Silico ◽

Cathepsin B ◽

Topoisomerase Iiα ◽

Enzymatic Inhibition ◽

Inhibition Studies

This work describes the enzymatic inhibitory activity of four novel Pd(ii) complexes towards topoisomerase IIα and cathepsins B and L. In silico studies agree well with the enhanced in vitro cathepsin B inhibition induced by compound 4 (58% at 10 μM).

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An In Silico and an In Vitro Inhibition Analysis of Glycogen Phosphorylase by Flavonoids, Styrylchromones, and Pyrazoles

Nutrients ◽

10.3390/nu14020306 ◽

2022 ◽

Vol 14 (2) ◽

pp. 306

Author(s):

Sónia Rocha ◽

Natália Aniceto ◽

Rita C. Guedes ◽

Hélio M. T. Albuquerque ◽

Vera L. M. Silva ◽

...

Keyword(s):

Inhibitory Activity ◽

In Silico ◽

Glycogen Phosphorylase ◽

Inhibitory Effect ◽

Docking Studies ◽

Potent Inhibitory Effect ◽

Key Enzyme ◽

Experimental Findings

Glycogen phosphorylase (GP) is a key enzyme in the glycogenolysis pathway. GP inhibitors are currently under investigation as a new liver-targeted approach to managing type 2 diabetes mellitus (DM). The aim of the present study was to evaluate the inhibitory activity of a panel of 52 structurally related chromone derivatives; namely, flavonoids, 2-styrylchromones, 2-styrylchromone-related derivatives [2-(4-arylbuta-1,3-dien-1-yl)chromones], and 4- and 5-styrylpyrazoles against GP, using in silico and in vitro microanalysis screening systems. Several of the tested compounds showed a potent inhibitory effect. The structure–activity relationship study indicated that for 2-styrylchromones and 2-styrylchromone-related derivatives, the hydroxylations at the A and B rings, and in the flavonoid family, as well as the hydroxylation of the A ring, were determinants for the inhibitory activity. To support the in vitro experimental findings, molecular docking studies were performed, revealing clear hydrogen bonding patterns that favored the inhibitory effects of flavonoids, 2-styrylchromones, and 2-styrylchromone-related derivatives. Interestingly, the potency of the most active compounds increased almost four-fold when the concentration of glucose increased, presenting an IC50 < 10 µM. This effect may reduce the risk of hypoglycemia, a commonly reported side effect of antidiabetic agents. This work contributes with important considerations and provides a better understanding of potential scaffolds for the study of novel GP inhibitors.

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In-vitro Cytotoxicity and Aromatase Inhibitory Activity of Flavonoids: Synthesis, Molecular Docking and In-silico ADME Prediction

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210827104406 ◽

2021 ◽

Vol 21 ◽

Author(s):

Umang Shah ◽

Samir Patel ◽

Mehul Patel ◽

Neeraj Jain ◽

Nilesh Pandey ◽

...

Keyword(s):

Breast Cancer ◽

Inhibitory Activity ◽

In Silico ◽

Computational Study ◽

Cancer Cell Line ◽

Inhibitory Effect ◽

In Vitro Cytotoxicity ◽

Spectroscopic Techniques ◽

Reference Drug

Background: Many natural and synthetic flavonoids have been studied and documented by inhibiting aromatase enzymes for their anti-cancer activity against breast carcinoma. The aromatase enzyme is a possible target for the estrogen's positive breast cancer receptor. Objective: Hence, a series of flavonoids have been synthesized and assessed for their in vitro cytotoxicity and aromatase inhibitory activity. Methods: 39 flavonoids were synthesized and characterized by spectroscopic techniques, and their computational study was performed using the maestro version of the Schrodinger. In-silico ADME properties were checked by QikPro software. A total of 18 compounds were evaluated based on the docking score using cytotoxicity assay in human breast cancer cell line MCF-7. Results: Of the 18 compounds tested, 07 compounds, namely 2b, 8b, 14b, 15b, 19b, 24b, and 30b flavonoids were found to be more active with their IC50 values of 20.73 μM, 1.636 μM, 16.08 μM, 22.02 μM, 15.75 μM, 0.345 μM and 16.08 μM, respectively, compared with the reference drug letrozole. The in-vitro aromatase inhibitory activity of six compounds 2b, 8b, 14b, 19b, 24b, and 30b was conducted using a fluorogenic assay kit. The values of IC50 for compounds 2b and 24b were found to be 0.31 μM and 0.36 μM, respectively. Conclusion: Therefore, it was concluded that compounds 2b and 24b had a potent inhibitory effect of aromatase compared with letrozole with an IC50 value of 0.86 μM. At the same time, the other compounds 8b, 14b, 30b, and 19b were considered to have similar aromatase inhibitory activity. Hence, their essential aromatase inhibitory activities make them good lead candidates for developing potent inhibitors of aromatase.

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Elucidation of Phosphodiesterase-1 Inhibitory Effect of Some Selected Natural Polyphenolics Using In Vitro and In Silico Methods

Current Topics in Medicinal Chemistry ◽

10.2174/1568026616666160824103615 ◽

2016 ◽

Vol 17 (4) ◽

pp. 412-417 ◽

Cited By ~ 9

Author(s):

Abdur Rauf ◽

Ilkay Erdogan Orhan ◽

Abdulselam Ertas ◽

Hamdi Temel ◽

Taibi Ben Hadda ◽

...

Keyword(s):

In Silico ◽

Inhibitory Effect ◽

In Silico Methods

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Chemical Composition, In Vitro and In Silico Antioxidant Potential of Melissa officinalis subsp. officinalis Essential Oil

Antioxidants ◽

10.3390/antiox10071081 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1081

Author(s):

Matilda Rădulescu ◽

Călin Jianu ◽

Alexandra Teodora Lukinich-Gruia ◽

Marius Mioc ◽

Alexandra Mioc ◽

...

Keyword(s):

Antioxidant Activity ◽

Chemical Composition ◽

Essential Oil ◽

In Silico ◽

Antioxidant Properties ◽

Radical Scavenging ◽

Inhibitory Effect ◽

Melissa Officinalis ◽

Β Carotene

The investigation aimed to study the in vitro and in silico antioxidant properties of Melissa officinalis subsp. officinalis essential oil (MOEO). The chemical composition of MOEO was determined using GC–MS analysis. Among 36 compounds identified in MOEO, the main were beta-cubebene (27.66%), beta-caryophyllene (27.41%), alpha-cadinene (4.72%), caryophyllene oxide (4.09%), and alpha-cadinol (4.07%), respectively. In vitro antioxidant properties of MOEO have been studied in 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical scavenging, and inhibition of β-carotene bleaching assays. The half-maximal inhibitory concentration (IC50) for the radical scavenging abilities of ABTS and DPPH were 1.225 ± 0.011 μg/mL and 14.015 ± 0.027 μg/mL, respectively, demonstrating good antioxidant activity. Moreover, MOEO exhibited a strong inhibitory effect (94.031 ± 0.082%) in the β-carotene bleaching assay by neutralizing hydroperoxides, responsible for the oxidation of highly unsaturated β-carotene. Furthermore, molecular docking showed that the MOEO components could exert an in vitro antioxidant activity through xanthine oxidoreductase inhibition. The most active structures are minor MOEO components (approximately 6%), among which the highest affinity for the target protein belongs to carvacrol.

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Potential Anticancer Lipoxygenase Inhibitors from the Red Sea-Derived Brown Algae Sargassum cinereum: An In-Silico-Supported In-Vitro Study

Antibiotics ◽

10.3390/antibiotics10040416 ◽

2021 ◽

Vol 10 (4) ◽

pp. 416

Author(s):

Sami I. Alzarea ◽

Abeer H. Elmaidomy ◽

Hani Saber ◽

Arafa Musa ◽

Mohammad M. Al-Sanea ◽

...

Keyword(s):

Red Sea ◽

Antiproliferative Activity ◽

Inhibitory Activity ◽

Brown Algae ◽

In Silico ◽

Active Sites ◽

In Vitro Study ◽

Lipoxygenase Inhibitors ◽

Phytochemical Investigation

LC-MS-assisted metabolomic profiling of the Red Sea-derived brown algae Sargassum cinereum “Sargassaceae” dereplicated eleven compounds 1–11. Further phytochemical investigation afforded two new aryl cresol 12–13, along with eight known compounds 14–21. Both new metabolites, along with 19, showed moderate in vitro antiproliferative activity against HepG2, MCF-7, and Caco-2. Pharmacophore-based virtual screening suggested both 5-LOX and 15-LOX as the most probable target linked to their observed antiproliferative activity. The in vitro enzyme assays revealed 12 and 13 were able to inhibit 5-LOX more preferentially than 15-LOX, while 19 showed a convergent inhibitory activity toward both enzymes. Further in-depth in silico investigation revealed the molecular interactions inside both enzymes’ active sites and explained the varying inhibitory activity for 12 and 13 toward 5-LOX and 15-LOX.

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Combined Ensemble Docking and Machine Learning in Identification of Therapeutic Agents with Potential Inhibitory Effect on Human CES1

Molecules ◽

10.3390/molecules24152747 ◽

2019 ◽

Vol 24 (15) ◽

pp. 2747 ◽

Cited By ~ 1

Author(s):

Eliane Briand ◽

Ragnar Thomsen ◽

Kristian Linnet ◽

Henrik Berg Rasmussen ◽

Søren Brunak ◽

...

Keyword(s):

Machine Learning ◽

Drug Interactions ◽

Scoring Function ◽

Docking Study ◽

Inhibitory Effect ◽

Therapeutic Agents ◽

Learning Approaches ◽

Ensemble Docking ◽

Ic50 Values

The human carboxylesterase 1 (CES1), responsible for the biotransformation of many diverse therapeutic agents, may contribute to the occurrence of adverse drug reactions and therapeutic failure through drug interactions. The present study is designed to address the issue of potential drug interactions resulting from the inhibition of CES1. Based on an ensemble of 10 crystal structures complexed with different ligands and a set of 294 known CES1 ligands, we used docking (Autodock Vina) and machine learning methodologies (LDA, QDA and multilayer perceptron), considering the different energy terms from the scoring function to assess the best combination to enable the identification of CES1 inhibitors. The protocol was then applied on a library of 1114 FDA-approved drugs and eight drugs were selected for in vitro CES1 inhibition. An inhibition effect was observed for diltiazem (IC50 = 13.9 µM). Three others drugs (benztropine, iloprost and treprostinil), exhibited a weak CES1 inhibitory effects with IC50 values of 298.2 µM, 366.8 µM and 391.6 µM respectively. In conclusion, the binding site of CES1 is relatively flexible and can adapt its conformation to different types of ligands. Combining ensemble docking and machine learning approaches improves the prediction of CES1 inhibitors compared to a docking study using only one crystal structure.

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Identification of Vinyl Sulfone Derivatives as EGFR Tyrosine Kinase Inhibitor: In Vitro and In Silico Studies

Molecules ◽

10.3390/molecules26082211 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2211

Author(s):

Thitinan Aiebchun ◽

Panupong Mahalapbutr ◽

Atima Auepattanapong ◽

Onnicha Khaikate ◽

Supaphorn Seetaha ◽

...

Keyword(s):

Tyrosine Kinase ◽

Inhibitory Activity ◽

In Silico ◽

Kinase Inhibitor ◽

Kinase Assay ◽

Vinyl Sulfone ◽

Egfr Tyrosine Kinase ◽

In Silico Studies ◽

Sulfone Derivatives

Epidermal growth factor receptor (EGFR), overexpressed in many types of cancer, has been proved as a high potential target for targeted cancer therapy due to its role in regulating proliferation and survival of cancer cells. In the present study, a series of designed vinyl sulfone derivatives was screened against EGFR tyrosine kinase (EGFR-TK) using in silico and in vitro studies. The molecular docking results suggested that, among 78 vinyl sulfones, there were eight compounds that could interact well with the EGFR-TK at the ATP-binding site. Afterwards, these screened compounds were tested for the inhibitory activity towards EGFR-TK using ADP-Glo™ kinase assay, and we found that only VF16 compound exhibited promising inhibitory activity against EGFR-TK with the IC50 value of 7.85 ± 0.88 nM. In addition, VF16 showed a high cytotoxicity with IC50 values of 33.52 ± 2.57, 54.63 ± 0.09, and 30.38 ± 1.37 µM against the A431, A549, and H1975 cancer cell lines, respectively. From 500-ns MD simulation, the structural stability of VF16 in complex with EGFR-TK was quite stable, suggesting that this compound could be a novel small molecule inhibitor targeting EGFR-TK.

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Andrographis paniculata (Burm. F.) Wall. Ex Nees, Andrographolide, and Andrographolide Analogues as SARS-CoV-2 Antivirals? A Rapid Review

Natural Product Communications ◽

10.1177/1934578x211016610 ◽

2021 ◽

Vol 16 (5) ◽

pp. 1934578X2110166

Author(s):

Xin Yi Lim ◽

Janice Sue Wen Chan ◽

Terence Yew Chin Tan ◽

Bee Ping Teh ◽

Mohd Ridzuan Mohd Abd Razak ◽

...

Keyword(s):

Inhibitory Activity ◽

In Silico ◽

Rna Binding ◽

Symptomatic Relief ◽

Andrographis Paniculata ◽

Spike Protein ◽

Rapid Review ◽

In Silico Studies

Drug repurposing is commonly employed in the search for potential therapeutic agents. Andrographis paniculata, a medicinal plant commonly used for symptomatic relief of the common cold, and its phytoconstituent andrographolide, have been repeatedly identified as potential antivirals against SARS-CoV-2. In light of new evidence emerging since the onset of the COVID-19 pandemic, this rapid review was conducted to identify and evaluate the current SARS-CoV-2 antiviral evidence for A. paniculata, andrographolide, and andrographolide analogs. A systematic search and screen strategy of electronic databases and gray literature was undertaken to identify relevant primary articles. One target-based in vitro study reported the 3CLpro inhibitory activity of andrographolide as being no better than disulfiram. Another Vero cell-based study reported potential SARS-CoV-2 inhibitory activity for both andrographolide and A. paniculata extract. Eleven in silico studies predicted the binding of andrographolide and its analogs to several key antiviral targets of SARS-CoV-2 including the spike protein-ACE-2 receptor complex, spike protein, ACE-2 receptor, RdRp, 3CLpro, PLpro, and N-protein RNA-binding domain. In conclusion, in silico and in vitro studies collectively suggest multi-pathway targeting SARS-CoV-2 antiviral properties of andrographolide and its analogs, but in vivo data are needed to support these predictions.

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