Том 24, № 4 (2024)
- Жылы: 2024
- Мақалалар: 6
- URL: https://ter-arkhiv.ru/1871-5206/issue/view/9991
Oncology
Discovery and Development of Promising Anticancer Agents via Computational and Experimental
235-235
Overview of the New Bioactive Heterocycles as Targeting Topoisomerase Inhibitors Useful Against Colon Cancer
Аннотация
Colorectal cancer (CRC) is the third most common cancer globally, with high mortality. Metastatic CRC is incurable in most cases, and multiple drug therapy can increase patients' life expectancy by 2 to 3 years. Efforts are being made to understand the relationship between topoisomerase enzymes and colorectal cancer. Some studies have shown that higher expression of these enzymes is correlated to a poor prognosis for this type of cancer. One of the primary drugs used in the treatment of CRC is Irinotecan, which can be used in monotherapy or, more commonly, in therapeutic schemes such as FOLFIRI (Fluorouracil, Leucovorin, and Irinotecan) and CAPIRI (Capecitabine and Irinotecan). Like Camptothecin, Irinotecan and other compounds have a mechanism of action based on the formation of a ternary complex with topoisomerase I and DNA providing damage to it, therefore leading to cell death. Thus, this review focused on the principal works published in the last ten years that demonstrate a correlation between the inhibition of different isoforms of topoisomerase and in vitro cytotoxic activity against CRC by natural products, semisynthetic and synthetic compounds of pyridine, quinoline, acridine, imidazoles, indoles, and metal complexes. The results revealed that natural compounds, semisynthetic and synthetic derivatives showed potential in vitro cytotoxicity against several colon cancer cell lines, and this activity was often accompanied by the ability to inhibit both isoforms of topoisomerase (I and II), highlighting that these enzymes can be promising targets for the development of new chemotherapy against CRC. Pyridine analogs were considered the most promising for this study, while the evaluation of the real potential of natural products was limited by the lack of information in their work. Moreover, the complexes, although promising, presented as the main limitation the lack of selectivity.
236-262
Identification of Novel EGFR Inhibitors for the Targeted Therapy of Colorectal Cancer Using Pharmacophore Modelling, Docking, Molecular Dynamic Simulation and Biological Activity Prediction
Аннотация
Background:Colorectal cancer (CRC) is considered the second deadliest cancer in the world. One of the reasons for the occurrence of this cancer is the deregulation of the Epidermal Growth Factor Receptor (EGFR), which plays a critical role in regulating cell division, persistence, differentiation, and migration. The overexpression of the EGFR protein leads to its dysregulation and causes CRC.
Objective:Hence, this work aims to identify and validate novel EGFR inhibitors for the treatment of colorectal cancer employing various computer aided techniques such as pharmacophore modeling, docking, molecular dynamic simulation and Quantitative Structure-Activity Relationship (QSAR) analysis.
Methods:In this work, a shared-featured ligand-based pharmacophore model was generated using the known inhibitors of EGFR. The best model was validated and screened against ZincPharmer and Maybridge databases, and 143 hits were obtained. Pharmacokinetic and toxicological properties of these hits were studied, and the acceptable ligands were docked against EGFR. The best five protein-ligand complexes with binding energy less than -5 kcal/mol were selected. The molecular dynamic simulation studies of these complexes were conducted for 100 nanoseconds (ns), and the results were analyzed. The biological activity of this ligand was calculated using QSAR analysis.
Results:The best complex with Root Mean Square Deviation (RMSD) 3.429 Å and Radius of Gyration (RoG) 20.181 Å was selected. The Root Mean Square Fluctuations (RMSF) results were also found to be satisfactory. The biological activity of this ligand was found to be 1.38 µM.
Conclusion:This work hereby proposes the ligand 2-((1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)oxy)-N- (1H-indol-4-yl)acetamide as a potential EGFR inhibitor for the treatment of colorectal cancer. The wet lab analysis must be conducted, however, to confirm this hypothesis.
263-279
Analysis of Inhibition Potential of Nimbin and its Analogs against NF-κB Subunits p50 and p65: A Molecular Docking and Molecular Dynamics Study
Аннотация
Background:Cancer remains the major cause of morbidity and mortality. The nuclear factor kappa-B (NF- κB) plays an indispensable role in cancer cell proliferation and drug resistance. The role of NF-κB is not only limited to tumor cell proliferation and suppression of apoptotic genes but it also induces EMT transition responsible for metastasis. Inhibition of the NF-κB pathway in cancer cells by herbal derivatives makes it a favorable yet promising target for cancer therapeutics.
Aim:The purpose of the study is to explore the inhibition potential of Nimbin and its analogs against NF-κB subunits p50 and p65.
Methods:In the present study, an herbal compound Nimbin and its derivative analogs were investigated to examine their impact on the p50 and p65 subunits of the NF-κB signaling pathway using in silico tools, namely molecular docking and simulation.
Results:The molecular docking analysis revealed that Nimbin and its analogs may bind to p50 and p65 subunits with dG bind values ranging from -33.23 to -50.49Kcal/mol. Interestingly, molecular dynamic simulation for the NO5-p65 complex displayed a stable conformation and convergence when compared to the NO4-p50 complex.
Conclusion:These results indicate that NO5 may have a potential inhibitory effect against NF-κB subunit p65, which needs to be further validated in in vitro and in vivo systems. Also, the results obtained emphasize and pave the way for exploring the Nimbin scaffold against NF-κB inhibition for cancer therapeutics.
280-287
Design and Pharmacophore Study of Triazole Analogues as Aromatase Inhibitors
Аннотация
Background:In current scenario breast cancer measured as one of the dangerous health issues. An effective therapeutic class of drug known as aromatase inhibitors (AIs) is dominant against estrogen receptorpositive breast cancer. However, there is an urgent need to create target-specific AIs with better anti-breast cancer profiles due to the increased toxicity and adverse effects related to currently existing anti-breast cancer drugs.
Objectives:In the present study, we have designed of 100 novel tiazole analogues as aromatase inhibitors their pharmacophoric features were explored.
Method:Molecular docking was applied to a series of 4-substituted-1, 2, 3-triazoles containing letrozole for their aromatase inhibitory effects. The aromatase inhibitory activity of the compound in a series varies in the range of (IC50 = 0.00831.26 µM). A hydrogen atom positioned at R1 of the triazole ring in compound (01) was responsible for the most potent compound (IC50 = 0.008 µM) in the series of 28 compounds as compared to letrozole. The self-organizing molecular field study was used to assess the molecular characteristics and biological activities of the compounds. The four models were developed using PLS and MLR methods. The PLS method was good for statistical analysis. The letrozole scaffold-based 100 compounds were designed by selecting an effective pharmacophore responsible for aromatase inhibitory activity. The designed compound was placed on the previous model as a test set, and its IC50 values were calculated.
Result:Hydrogen bonds were established between the potent molecule (01) and the essential residues Met 374 and Arg 115, which were responsible for the aromatase-inhibiting action. Cross-validated q2 (0.6349) & noncross- validated r2 (0.7163) were discovered in the statistical findings as having reliable predictive power. Among 100 designed compounds, seven compounds showed good aromatase inhibitory activities.
Conclusion:The additional final SOMFA model created for the interactions between the aromatase and the triazole inhibitors may be helpful for future modification and enhancement of the inhibitors of this crucial enzyme.
288-303
Exploring the Synergistic Effect of Sildenafil and Green Tea Polyphenols on Breast Cancer Stem Cell-like Cells and their Parental Cells: A Potential Novel Therapeutic Approach
Аннотация
Background::Many cancer studies have intensely focused on the role of diet, among other factors involved in cancer establishment. The positive effect of green tea polyphenols (GTP) on controlling breast cancer cells has been reported in several studies. Cancer stem cell-like cells (CSC-LCs) possessing self-renewal, metastatic, and drug-resistant capacities are considered prominent therapeutic targets. In many tumors, inducible nitric oxide synthase (iNOS) expression levels are high; however, they have a dual effect on breast cancer pathogenesis.
Objective::This study aimed to investigate the cytotoxicity of the iNOS agonist (Sildenafil) and antagonist (LNAME), both alone and in combination with GTP, on MDA-MB-231, CD44+/CD24- CSC-LCs, and their parental cells (MCF-7).
Methods::The cell viability assay has been studied using the MTT assay. To analyze drug-drug combinations, CompuSyn and Combenefit software were used. The cytotoxicity mechanism was determined using flow cytometric analysis.
Results::L-NAME and GTP showed a synergistic effect on MDA-MB-231 and CSC-LCs. Such an effect was not observed on MCF-7. Sildenafil and GTP, on the other hand, showed synergistic cytotoxicity in all the cells mentioned above. Flow cytometric tests resulted in more than 70% apoptosis in MDA-MB-231 and MCF-7. Also, sub-G1 arrest among MCF-7 cells and a considerable decrease in ROS production by MDA-MB-231 cells following treatment with Sildenafil and GTP were observed.
Conclusion::Sildenafil, in combination with flavonoids, may be considered a novel strategy for cancer treatment.
304-315