Structural binding perspectives of a major tobacco alkaloid, nicotine, and its metabolite cotinine with sex‐steroid nuclear receptors

Rehan, Mohd; Ahmad, Ejaz; Beg, M.A.

doi:10.1002/jat.3993

Cited by 6 publications

(5 citation statements)

References 42 publications

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“…The native bound ligands were used as clue for the binding site and the residues around 10 Å of the native ligands were used as the binding site region for generating docking grid. Finally, the molecular docking of the compounds was performed using the rigid ligand docking option with default parameters and the docking poses and predicted results were generated, as detailed previously [ 36 ].…”

Section: Methodsmentioning

confidence: 99%

Organotin Antifouling Compounds and Sex-Steroid Nuclear Receptor Perturbation: Some Structural Insights

Beg

Zargar

et al. 2022

Toxics

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Organotin compounds (OTCs) are a commercially important group of organometallic compounds of tin used globally as polyvinyl chloride stabilizers and marine antifouling biocides. Worldwide use of OTCs has resulted in their ubiquitous presence in ecosystems across all the continents. OTCs have metabolic and endocrine disrupting effects in marine and terrestrial organisms. Thus, harmful OTCs (tributyltin) have been banned by the International Convention on the Control of Harmful Antifouling Systems since 2008. However, continued manufacturing by non-member countries poses a substantial risk for animal and human health. In this study, structural binding of common commercial OTCs, tributyltin (TBT), dibutyltin (DBT), monobutyltin (MBT), triphenyltin (TPT), diphenyltin (DPT), monophenyltin (MPT), and azocyclotin (ACT) against sex-steroid nuclear receptors, androgen receptor (AR), and estrogen receptors (ERα, ERβ) was performed using molecular docking and MD simulation. TBT, DBT, DPT, and MPT bound deep within the binding sites of AR, ERα, and Erβ, showing good dock score, binding energy and dissociation constants that were comparable to bound native ligands, testosterone and estradiol. The stability of docking complex was shown by MD simulation of organotin/receptor complex with RMSD, RMSF, Rg, and SASA plots showing stable interaction, low deviation, and compactness of the complex. A high commonality (50–100%) of interacting residues of ERα and ERβ for the docked ligands and bound native ligand (estradiol) indicated that the organotin compounds bound in the same binding site of the receptor as the native ligand. The results suggested that organotins may interfere with the natural steroid/receptor binding and perturb steroid signaling.

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Section: Methodsmentioning

confidence: 99%

Organotin Antifouling Compounds and Sex-Steroid Nuclear Receptor Perturbation: Some Structural Insights

Beg

Zargar

et al. 2022

Toxics

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“…Previous studies involving nicotine and/or its metabolites on structural binding interactions against hormone carrier proteins such as SHBG, CBG, and TBG are not available to the best of our knowledge. However, recent structural binding and previous in vitro competitive binding studies have shown inhibitory interactions of nicotine and/or cotinine against steroid nuclear receptors [40,[50][51][52][53]. Nicotine is a powerful and addictive toxicant and has been reported to disturb the reproductive hormone levels including the SHBG levels in the circulation [54,55].…”

Section: Hormone Relationships Relevance and Conclusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…and progesterone, whereas TBG is responsible for the transport and availability of thyroid hormones (thyroxine, triiodothyronine). Computational methods have been increasingly used for the prediction of binding pose and molecular interactions of ligands with their target protein molecules, for designing novel inhibitors, and/or as an aid for designing experimental and clinical studies [38][39][40][41]. In the present study, the tobacco alkaloid nicotine and its three endogenous metabolites, i.e., cotinine, trans-3′-hydroxycotinine, and 5′-hydroxycotinine (Figure 1) were explored for their structural binding and inhibitory interactions against the three endocrine transport proteins (SHBG, TBG, and CBG) using computational methods.…”

Section: Introductionmentioning

confidence: 99%

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Potential Disruption of Systemic Hormone Transport by Tobacco Alkaloids Using Computational Approaches

Rehan

Zargar

Sheikh

et al. 2022

Toxics

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Tobacco/nicotine is one of the most toxic and addictive substances and continues to pose a significant threat to global public health. The harmful effects of smoking/nicotine affect every system in the human body. Nicotine has been associated with effects on endocrine homeostasis in humans such as the imbalance of gonadal steroid hormones, adrenal corticosteroid hormones, and thyroid hormones. The present study was conducted to characterize the structural binding interactions of nicotine and its three important metabolites, cotinine, trans-3′-hydroxycotinine, and 5′-hydroxycotinine, against circulatory hormone carrier proteins, i.e., sex-hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), and thyroxine-binding globulin (TBG). Nicotine and its metabolites formed nonbonded contacts and/or hydrogen bonds with amino acid residues of the carrier proteins. For SHBG, Phe-67 and Met-139 were the most important amino acid residues for nicotine ligand binding showing the maximum number of interactions and maximum loss in ASA. For CBG, Trp-371 and Asn-264 were the most important amino acid residues, and for TBG, Ser-23, Leu-269, Lys-270, Asn-273, and Arg-381 were the most important amino acid residues. Most of the amino acid residues of carrier proteins interacting with nicotine ligands showed a commonality with the interacting residues for the native ligands of the proteins. Taken together, the results suggested that nicotine and its three metabolites competed with native ligands for binding to their carrier proteins. Thus, nicotine and its three metabolites may potentially interfere with the binding of testosterone, estradiol, cortisol, progesterone, thyroxine, and triiodothyronine to their carrier proteins and result in the disbalance of their transport and homeostasis in the blood circulation.

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“…5 Nicotine is excreted as cotinine and 3′-hydroxy-cotinine in the urine, in body fluids such as blood and saliva, or the nails and hair. 6 Therefore, it can be used to measure recent exposure to nicotine, even low doses; a high concentration is usually observed 4 to 8 hours after exposure. 7 In addition, measurement of urinary cotinine (UC) is relatively inexpensive and easy and has high sensitivity and precision.…”

Section: Introductionmentioning

confidence: 99%

Factors Associated With the Differences Between Self-Report Smoking and Urinary Cotinine Criteria

Lee

Yoon

Lee

et al. 2021

Asia Pac J Public Health

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During self-reporting, respondents underreport their smoking status for various reasons. We aimed to evaluate the difference between smoking status self-reporting and urinary cotinine tests in Korea respondents. Logistic regression analyses were performed to identify factors associated with the differences between self-reporting and urinary cotinine criteria. The dependent variable was the underreporting of smoking status; independent variables were sociodemographic, health status, and secondhand smoke (SHS) exposure. Total underreporting was 3.6% when Cot ≥164 and 4.0% when Cot-variable (classified) criteria underreported. Positive associations were found between smoking and age, education, drinking, and SHS. Underreporting in the nonsmoker group (odds ratio [OR] = 2.336; confidence interval [CI] = 1.717-3.179) was significantly associated with SHS, but this difference was nonsignificant in the ex-smoker group (OR = 1.184; CI = 0.879-1.638). Underreporting was 3.6% to 4.0%, and C-statistics was about 0.7, indicating that outcomes could be classified. SHS in nonsmokers was positively associated with underreporting; however, only the nonsmoker group had positive associations, demonstrating unintentional underreporting due to SHS.

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Structural binding perspectives of a major tobacco alkaloid, nicotine, and its metabolite cotinine with sex‐steroid nuclear receptors

Cited by 6 publications

References 42 publications

Organotin Antifouling Compounds and Sex-Steroid Nuclear Receptor Perturbation: Some Structural Insights

Organotin Antifouling Compounds and Sex-Steroid Nuclear Receptor Perturbation: Some Structural Insights

Potential Disruption of Systemic Hormone Transport by Tobacco Alkaloids Using Computational Approaches

Factors Associated With the Differences Between Self-Report Smoking and Urinary Cotinine Criteria

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