Identification and characterization of in silico, in vivo, in vitro, and reactive metabolites of infigratinib using LC-ITMS: bioactivation pathway elucidation and in silico toxicity studies of its metabolites

Al-Shakliah, Nasser S.; Attwa, Mohamed W.; Kadi, Adnan A.; AlRabiah, Haitham

doi:10.1039/c9ra10871h

Cited by 34 publications

(22 citation statements)

References 42 publications

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“…To predict the atomic sites, and to calculate the probability of the cytochrome p450 enzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) undergoing metabolic modifications and metabolism mediated by human liver microsomes, we performed an in silico approach using the online tool Xenosite [ 14 , 15 , 16 , 17 , 18 ]. The results displayed the main metabolic sites within the chemical structures of 6-gingerol and 6-shogaol, represented using a color scale where red represents a greater probability of undergoing a metabolic transformation by any of the isoenzymes.…”

Section: Resultsmentioning

confidence: 99%

Active Compounds in Zingiber officinale as Possible Redox Inhibitors of 5-Lipoxygenase Using an In Silico Approach

Ley-Martínez

Ortega-Valencia

García-Barradas

et al. 2022

IJMS

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5-Lipoxygenase (5-LOX) converts arachidonic acid to lipidic inflammatory mediators such as leukotrienes (LTs). In diseases such as asthma, LTs contribute to a physiopathology that could be reverted by blocking 5-LOX. Natural products with anti-inflammatory potential such as ginger have been used as nutraceuticals since ancient times. 6-Gingerol and 6-shogaol are the most abundant compounds in the ginger rhizome; they possess anti-inflammatory, antioxidant, and chemopreventive properties. In the present study, 6-gingerol and 6-shogaol structures were analyzed and compared with two commercial 5-LOX inhibitors (zileuton and atreleuton) and with other inhibitor candidates (3f, NDGA, CP 209, caffeic acid, and caffeic acid phenethyl ester (CAPE)). The pharmacokinetics and toxicological properties of 6-gingerol, 6-shogaol, and the other compounds were evaluated. Targeted molecular coupling was performed to identify the optimal catalytic pocket for 5-LOX inhibition. The results showed that 6-gingerol and 6-shogaol follow all of the recommended pharmacokinetic parameters. These compounds could be inhibitors of 5-LOX because they present specific interactions with the residues involved in molecular inhibition. The current study demonstrated the potential of 6-gingerol and 6-shogaol as anti-inflammatory agents that inhibit 5-LOX, as they present a high level of performance in the toxicological analysis and could be catabolized by the cytochrome p450 enzymatic complex; however, 6-gingerol was superior in safety compared to 6-shogaol.

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Section: Resultsmentioning

confidence: 99%

Active Compounds in Zingiber officinale as Possible Redox Inhibitors of 5-Lipoxygenase Using an In Silico Approach

Ley-Martínez

Ortega-Valencia

García-Barradas

et al. 2022

IJMS

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“…Notably, it has been accorded both orphan drug designation and priority review status by the U.S Food and Drug Administration (FDA) for the treatment of advanced cholangiocarcinomaa rare malignancy plagued with an extremely poor prognosis and limited therapeutic options (Mosconi et al, 2009). However, a recent study has identified several putative reactive metabolites of INF that are proposed to have arisen from cytochrome P450 enzyme (P450)-mediated metabolic activation of its N-ethyl piperazine and dimethoxybenzene ring moieties (Al-Shakliah et al, 2020). In that regard, the P450s are a ubiquitous family of hemoproteins that serve as one of the major drivers of xenobiotic oxidative metabolism in the human body (Guengerich, 2001;Zanger and Schwab, 2013).…”

Section: Introductionmentioning

confidence: 99%

Infigratinib Is a Reversible Inhibitor and Mechanism-Based Inactivator of Cytochrome P450 3A4

et al. 2021

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“…What is more, ion trap spectrometers don't provide such high mass accuracy as TOF or Q‐TOF mass spectrometers. Therefore, application of ion trap instruments in metabolic stability studies is severely limited, and as there were studies using this method to assess metabolic stability [61–64], this method was not eagerly used in recent studies.…”

Section: Separation Techniques Used In Metabolic Stability Estimationmentioning

confidence: 99%

“…In paid options, Stardrop software seems to be one of the most valuable options. Apart from predicting sites of metabolism, Stardrop can also predict P450 metabolism, and is a valuable in silico tool to develop ADME QSAR models and explore metabolism in many creative pathways, depending on the chosen package [54,58,64,93–96].…”

Section: Chemometric Techniques Used In Metabolic Stability Model Devmentioning

confidence: 99%

Metabolic stability studies of lead compounds supported by separation techniques and chemometrics analysis

Ulenberg

Bączek

2020

J of Separation Science

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With metabolism being one of the main routes of drug elimination from the body (accounting for removal of around 75% of known drugs), it is crucial to understand and study metabolic stability of drug candidates. Metabolically unstable compounds are uncomfortable to administer (requiring repetitive dosage during therapy), while overly stable drugs increase risk of adverse drug reactions. Additionally, biotransformation reactions can lead to formation of toxic or pharmacologically active metabolites (either less‐active than parent drug, or even with different action). There were numerous approaches in estimating metabolic stability, including in vitro, in vivo, in silico, and high‐throughput screening to name a few. This review aims at describing separation techniques used in in vitro metabolic stability estimation, as well as chemometric techniques allowing for creation of predictive models which enable high‐throughput screening approach for estimation of metabolic stability. With a very low rate of drug approval, it is important to understand in silico methods that aim at supporting classical in vitro approach. Predictive models that allow assessment of certain biological properties of drug candidates allow for cutting not only cost, but also time required to synthesize compounds predicted to be unstable or inactive by in silico models.

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Identification and characterization of in silico, in vivo, in vitro, and reactive metabolites of infigratinib using LC-ITMS: bioactivation pathway elucidation and in silico toxicity studies of its metabolites

Abstract: An in silico web designer tool was utilized to guide laboratory work for infigratinib metabolism. Sixteen metabolites of infigratinib and seven reactive intermediates (three iminium ions and four 1,4 benzoquinones) were characterized using LC-ITMS.

Cited by 34 publications

References 42 publications

Active Compounds in Zingiber officinale as Possible Redox Inhibitors of 5-Lipoxygenase Using an In Silico Approach

Active Compounds in Zingiber officinale as Possible Redox Inhibitors of 5-Lipoxygenase Using an In Silico Approach

Infigratinib Is a Reversible Inhibitor and Mechanism-Based Inactivator of Cytochrome P450 3A4

Metabolic stability studies of lead compounds supported by separation techniques and chemometrics analysis

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