scholarly journals Triclocarban and Triclosan Inhibit Human Aromatase via Different Mechanisms

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Huitao Li ◽  
Yu Zhao ◽  
Lanlan Chen ◽  
Ying Su ◽  
Xiaoheng Li ◽  
...  
Keyword(s):  
Endocrine Disruptors ◽  
Reproductive Function ◽  
Docking Study ◽  
Binding Pocket ◽  
Personal Care ◽  
Industrial Products ◽  
Steroid Binding ◽  
Human Aromatase ◽  
Important Enzyme

Human aromatase (CYP19A1) is an important enzyme, which produces estrogen from androgen for maintaining the female reproductive function and pregnancy. Triclocarban and triclosan are antimicrobial chemicals added to personal care, household, and industrial products. They could be endocrine disruptors and may disrupt human CYP19A1 activity. In the present study, we investigated the effects of triclocarban and triclosan on estradiol production and human CYP19A1 activity in JEG-3 cells. Triclocarban and triclosan reduced estradiol production in JEG-3 cells. Triclocarban and triclosan inhibited human CYP19A1 with IC50values of 15.81 and 6.26 μM, respectively. Triclosan competitively inhibited CYP19A1, while triclocarban noncompetitively inhibited this enzyme. Docking study showed that triclosan bound to the steroid-binding pocket of CYP19A1, while triclocarban was off this target, suggesting a different mechanism. In conclusion, triclocarban and triclosan are inhibitors of human CYP19A1.

scholarly journals Effects of Fungicides on Rat’s Neurosteroid Synthetic Enzymes

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Xiuwei Shen ◽  
Fan Chen ◽  
Lanlan Chen ◽  
Ying Su ◽  
Ping Huang ◽  
...  
Keyword(s):  
Endocrine Disruptors ◽  
Fungal Infections ◽  
Hydroxysteroid Dehydrogenase ◽  
Docking Study ◽  
Binding Pocket ◽  
Retinol Dehydrogenase ◽  
Synthetic Enzymes ◽  
Environmental Endocrine Disruptors ◽  
Agricultural Plants ◽  
Steroid Binding

Exposure to environmental endocrine disruptors may interfere with nervous system’s activity. Fungicides such as tebuconazole, triadimefon, and vinclozolin have antifungal activities and are used to prevent fungal infections in agricultural plants. In the present study, we studied effects of tebuconazole, triadimefon, and vinclozolin on rat’s neurosteroidogenic 5α-reductase 1 (5α-Red1), 3α-hydroxysteroid dehydrogenase (3α-HSD), and retinol dehydrogenase 2 (RDH2). Rat’s 5α-Red1, 3α-HSD, and RDH2 were cloned and expressed in COS-1 cells, and effects of these fungicides on them were measured. Tebuconazole and triadimefon competitively inhibited 5α-Red1, with IC50 values of 8.670 ± 0.771 × 10−6 M and 17.390 ± 0.079 × 10−6 M, respectively, while vinclozolin did not inhibit the enzyme at 100 × 10−6 M. Triadimefon competitively inhibited 3α-HSD, with IC50 value of 26.493 ± 0.076 × 10−6 M. Tebuconazole and vinclozolin weakly inhibited 3α-HSD, with IC50 values about 100 × 10−6 M, while vinclozolin did not inhibit the enzyme even at 100 × 10−6 M. Tebuconazole and triadimefon weakly inhibited RDH2 with IC50 values over 100 × 10−6 M and vinclozolin did not inhibit this enzyme at 100 × 10−6 M. Docking study showed that tebuconazole, triadimefon, and vinclozolin bound to the steroid-binding pocket of 3α-HSD. In conclusion, triadimefon potently inhibited rat’s neurosteroidogenic enzymes, 5α-Red1 and 3α-HSD.

scholarly journals Pesticides as endocrine distruptors of the reproductive system (literature review and own research)

2021 ◽  
pp. 49-62
Author(s):  
Ninel Shepelska ◽  
Mykola Prodanchuk ◽  
Yana Kolianchuk
Keyword(s):  
Reproductive Health ◽  
Endocrine Disruptors ◽  
Reproductive System ◽  
Reproductive Toxicity ◽  
Endocrine System ◽  
Reproductive Function ◽  
Dose Dependence ◽  
Animal Cells ◽  
Wide Range ◽  
The Impact

Currently, one of the main threats to human health is undoubtedly endocrine disruptors (ED), since they directly disrupt the processes of homeostasis maintenance, controlled by the endocrine system, the purpose of which is to maintain normal functions and development in a constantly changing environment. Pesticides can disrupt the physiological functioning of many endocrine axes, including the endocrine mechanisms that ensure reproductive health. It should be noted that research aimed at preventing chemically induced reproductive disorders in the human population is one of the central areas of preventive medicine, both in terms of their importance and the complexity of the tasks being solved. Analysis and generalization of the results of our own long-term studies have shown that the selective, and, therefore, the most dangerous toxicity of pesticides for the reproductive system is determined by endocrine-mediated mechanisms of etiopathogenesis. The low level of doses inducing pathological changes in reproductive function in our studies fully confirms one of the universal signs inherent in endocrine-distruptive compounds. The above examples demonstrate a wide range of possible endocrine-mediated mechanisms of reproductive toxicity of pesticides - endocrine disruptors. However, it is very important to note that low doses may be more effective in changing some endpoints compared to high (toxic) doses. Currently, several mechanisms have been identified and studied that demonstrate how hormones and ED induce non-monotonic reactions in animal cells, tissues and organs. The reproductive system, the functioning of which is ensured by a fine balancing of the action of androgens and estrogens, is one of the systems that presents a unique opportunity for modeling a non-monotonic dose dependence. All of the above indicates the extreme danger of the impact of hormonally active agents on the reproductive health of a person and his offspring. At the same time, the threat of endocrine-mediated disorders for subsequent generations can also be realized through the induction of mechanisms of development of epigenetic transgenerational effects. Taking into account the results of studies of the mechanisms of the ED destructive action, as well as their ability to induce non-monotonic dose dependence at an extremely low dose level, it should be admitted that, apparently, there is a need to revise the paradigm of methodological approaches to the regulation of pesticides with endocrine-disruptive properties. Key words: pesticides, endocrine disruptors, reproductive system

Synthesis of Some Novel Benzimidazole Derivatives as Anticancer Agent, and Evaluation for CDK2 Inhibition Activity

2021 ◽  
Vol 17 ◽  
Author(s):  
Rania Helmy Abd El-Hameed ◽  
Samar Said Fatahala ◽  
Amira Ibrahim Sayed
Keyword(s):  
Cell Lines ◽  
Docking Study ◽  
Binding Pocket ◽  
Kinase Assay ◽  
Benzimidazole Derivatives ◽  
Pharmacological Activities ◽  
Anticancer Compounds ◽  
Anti Cancer ◽  
Hct 116

Background: Thiobezimidazoles reveal various pharmacological activities due to similarities with many natural and synthetic molecules, they can easily interact with biomolecules of living systems. Objective: A series of substituted 2-thiobezimidazoles has been synthesized .Twelve final compounds were screened for in vitro anti-cancer activities against sixty different cell-lines. Methods: The spectral data of the synthesized compounds were characterized. Docking study for active anticancer compounds and CDK2/CyclinA2 Kinase assay against standard reference; Imatinib were performed. Results: Two compounds (3c&3l) from the examined series revealed effective antitumor activity in vitro against two-cancer cell lines (Colon Cancer (HCT-116) and Renal Cancer (TK-10). The docking study of synthesized molecules discovered a requisite binding pose in CDK-ATP binding pocket. 3c &3l were promoted in the CDK2/CyclinA2 Kinase assay against standard reference Imatinib. Conclusion: Against all tested compounds ; two compounds 3c &3l were found active against two types of cell-lines.

scholarly journals Gymnema Sylvestre A- Potential Inhibitor of COVID-19 Main Protease by MD Simulation Study

2020 ◽  
Author(s):  
Senthil Kumar Subramani ◽  
Yash Gupta ◽  
Manish Manish ◽  
GBKS Prasad
Keyword(s):  
Md Simulation ◽  
Docking Study ◽  
Binding Pocket ◽  
Gymnema Sylvestre ◽  
Molecular Docking Study ◽  
Main Protease ◽  
Strong Candidate ◽  
The Stability ◽  
Potential Inhibitors ◽  
Domain I

Gymnema sylvestre (GS) is one of the herbal plant used since in ancient times. The present study aimed to assess bioactive compounds GS mainly gymnemic acids as potential inhibitors for COVID-19 against Mpro enzyme using a molecular docking study. The docking score observed between -53.4 to - 42.4 of all gymnemic acids and its derivatives. Molecular Dynamics (MD) simulation studies carried out at 100ns supported the stability of GS molecules within the binding pocket. RMSD score of less than 3.6. mainly, our results supported that these GS molecules bind to the domain I & II, and domain II-III linker of 3CLpro enzyme, suggesting its suitability as strong candidate for therapeutic against COVID-19. <br>

scholarly journals Novel Structural Mechanism of Glutathione as a Potential Peptide Inhibitor to the Main Protease (Mpro): CoviD-19 Treatment, Molecular Docking and SAR Study

2020 ◽  
Author(s):  
abde lina ◽  
Khedidja BENAROUS ◽  
Mohamed Yousfi
Keyword(s):  
Molecular Docking ◽  
Pantothenic Acid ◽  
Vitamin B1 ◽  
Docking Study ◽  
Binding Pocket ◽  
Molecular Docking Study ◽  
Structural Mechanism ◽  
Discovery Studio ◽  
Main Protease ◽  
Sar Study

2019-nCoV Coronavirus spread all over the world and obliged one billion people in open confinement, no treatments or vaccine have been yet found against this pandemic. The Main Protease (M<sup>pro</sup>) is an attractive drug target, because it is the essential protein for the virus invasion. This study aims to test in silico the effect of five vitamins and a natural antioxidant against M<sup>pro</sup>, using molecular docking study, with Autodock Vina and Discovery Studio visualizer softwares. The used inhibitors were chosen based on their beneficial properties such as Tocopherol (vitamin E), Thiamine (vitamin B1), Pantothenic acid (vitamin B5), Pyridoxine (vitamin B6), Biotin (vitamin B7), and Glutathione (GSH), the best inhibitor pose was chosen based on the repetition ratio (RR) and the minimum affinity energy value (MEV). The results show that Glutathione is the best inhibitor model among the other tested vitamins in the active site of M<sup>pro</sup> with a RR value of 94% and MEV of - 5.5 kcal/mol, the compatibility of Glutathione structure inside the binding pocket as a tripeptide model found to be similar to the native ligand of M<sup>pro</sup>. Moreover, Thiamine, Biotin, and Tocopherol are saved as satisfied inhibitors to M<sup>pro</sup>, Pyridoxine was the weakest inhibitor. Depending on this result, we recommend the use of Glutathione and vitamin B family as a supportive strategy for the treatment of COVID-19.<br>

scholarly journals Novel Structural Mechanism of Glutathione as a Potential Peptide Inhibitor to the Main Protease (Mpro): CoviD-19 Treatment, Molecular Docking and SAR Study

2020 ◽  
Author(s):  
abde lina ◽  
Khedidja BENAROUS ◽  
Mohamed Yousfi
Keyword(s):  
Molecular Docking ◽  
Pantothenic Acid ◽  
Vitamin B1 ◽  
Docking Study ◽  
Binding Pocket ◽  
Molecular Docking Study ◽  
Structural Mechanism ◽  
Discovery Studio ◽  
Main Protease ◽  
Sar Study

2019-nCoV Coronavirus spread all over the world and obliged one billion people in open confinement, no treatments or vaccine have been yet found against this pandemic. The Main Protease (M<sup>pro</sup>) is an attractive drug target, because it is the essential protein for the virus invasion. This study aims to test in silico the effect of five vitamins and a natural antioxidant against M<sup>pro</sup>, using molecular docking study, with Autodock Vina and Discovery Studio visualizer softwares. The used inhibitors were chosen based on their beneficial properties such as Tocopherol (vitamin E), Thiamine (vitamin B1), Pantothenic acid (vitamin B5), Pyridoxine (vitamin B6), Biotin (vitamin B7), and Glutathione (GSH), the best inhibitor pose was chosen based on the repetition ratio (RR) and the minimum affinity energy value (MEV). The results show that Glutathione is the best inhibitor model among the other tested vitamins in the active site of M<sup>pro</sup> with a RR value of 94% and MEV of - 5.5 kcal/mol, the compatibility of Glutathione structure inside the binding pocket as a tripeptide model found to be similar to the native ligand of M<sup>pro</sup>. Moreover, Thiamine, Biotin, and Tocopherol are saved as satisfied inhibitors to M<sup>pro</sup>, Pyridoxine was the weakest inhibitor. Depending on this result, we recommend the use of Glutathione and vitamin B family as a supportive strategy for the treatment of COVID-19.<br>

scholarly journals Based on the Virtual Screening of Multiple Pharmacophores, Docking and Molecular Dynamics Simulation Approaches toward the Discovery of Novel HPPD Inhibitors

2020 ◽  
Vol 21 (15) ◽  
pp. 5546
Author(s):  
Ying Fu ◽  
Tong Ye ◽  
Yong-Xuan Liu ◽  
Jian Wang ◽  
Fei Ye
Keyword(s):  
Coulomb Force ◽  
Docking Study ◽  
Binding Mode ◽  
Homogentisic Acid ◽  
Dynamics Simulation ◽  
Catabolic Pathway ◽  
Molecular Docking Study ◽  
Generalized Born ◽  
Pharmacophore Models ◽  
Important Enzyme

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an iron-dependent non-heme oxygenase involved in the catabolic pathway of tyrosine, which is an important enzyme in the transformation of 4-hydroxyphenylpyruvic acid to homogentisic acid, and thus being considered as herbicide target. Within this study, a set of multiple structure-based pharmacophore models for HPPD inhibitors were developed. The ZINC and natural product database were virtually screened, and 29 compounds were obtained. The binding mode of HPPD and its inhibitors obtained through molecular docking study showed that the residues of Phe424, Phe381, His308, His226, Gln307 and Glu394 were crucial for activity. Molecular-mechanics-generalized born surface area (MM/GBSA) results showed that the coulomb force, lipophilic and van der Waals (vdW) interactions made major contributions to the binding affinity. These efforts will greatly contribute to design novel and effective HPPD inhibitory herbicides.

In-Silico QSAR Modelling of Predicted Rho Kinase Inhibitors Against Cardio Vascular Diseases

2019 ◽  
Vol 15 (5) ◽  
pp. 421-432
Author(s):  
Seema Kesar ◽  
Sarvesh Paliwal ◽  
Swapnil Sharma ◽  
Pooja Mishra ◽  
Monika Chauhan ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Inflammatory Diseases ◽  
Smooth Muscles ◽  
Rho Kinase ◽  
Vascular Diseases ◽  
Docking Study ◽  
Binding Pocket ◽  
Quantitative Structure Activity Relationship ◽  
Structural Features ◽  
Qsar Analysis

Background: : Rho-kinase is an essential downstream target of GTP-binding protein RhoA, and plays a crucial role in the calcium-sensitization pathway. Rho-kinase pathway is critically involved in phosphorylation state of myosin light chain, leading to increased contraction of smooth muscles. Inhibition of this pathway has turned out to be a promising target for several indications such as cardiovascular diseases, glaucoma and inflammatory diseases. Methods:: The present work focuses on a division-based 2D quantitative structure-activity relationship (QSAR) analysis along with a docking study to predict structural features that may be essential for the enhancement of selectivity and potency of the target compounds. Furthermore, a set of indoles and azaindoles were also projected based on the regression equation as novel developments. Molecular docking was applied for exploring the binding sites of the newly predicted set of compounds with the receptor. Results: : Results of the docked conformations suggested that introduction of non-bulky and substituted groups in the hinge region of ROCK-II ATP binding pocket would improve the activity by decreasing the bulkiness or length of the compounds. Conclusion: : ADME studies were performed to ascertain the novelty and drug-like properties of the designed molecules, respectively.

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