EGFR, HER2 target based molecular docking analysis, in vitro screening of 2, 4, 5-trisubstituted imidazole derivatives as potential anti-oxidant and cytotoxic agents

Guda, Ramu; Kumar, Ashok; Korra, Rajashekar; Balaji, S.; Dayakar, G; Palabindela, Rambabu; Myadaraveni, Prabhakar; Yellu, Narsimha Reddy; Kasula, Mamatha

doi:10.1016/j.jphotobiol.2017.09.010

Cited by 23 publications

(9 citation statements)

References 65 publications

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“…As co-expression of different ErbB receptors occurs commonly, 87% of EGFR positive tumors also express HER2 [51]. Due to all of the above, EGFR and HER2 receptors have been selected in the literature [53] to relate in vitro anti-cancer activity to in silico docking calculations. In this last reference, the results from the docking of imidazole derivatives against EGFR and HER2 showed a general good agreement with their cytotoxic results.…”

Section: Molecular Dockingmentioning

confidence: 99%

In Vitro and In Silico Screening of 2,4,5-Trisubstituted Imidazole Derivatives as Potential Xanthine Oxidase and Acetylcholinesterase Inhibitors, Antioxidant, and Antiproliferative Agents

et al. 2020

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The employment of privileged scaffolds in medicinal chemistry supplies scientists with a solid start in the search for new and improved therapeutic molecules. One of these scaffolds is the imidazole ring, from which several derivatives have shown a wide array of biological activities. A series of 2,4,5-triphenyl imidazole derivatives were synthesized, characterized, and evaluated in vitro as antioxidant molecules using 1,1-diphenyl-2-picrylhydrazyl (DPPH.) and 2-2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS.+) assays, acetylcholinesterase (AChE) and xanthine oxidase (XO) inhibitors as well as antiproliferative agents. Additional in silico studies such as docking and determination of their absorption, distribution, metabolism, and excretion (ADME) properties were calculated. Compounds 3 and 10 were the most active antioxidants in both the DPPH and ABTS assays (EC50 of 0.141 and 0.174 mg/mL, and 0.168 and 0.162 mg/mL, respectively). In the enzymatic inhibition, compound 1 showed the best activity, inhibiting 25.8% of AChE at a concentration of 150 μg/mL, and compound 3 was the most active XO inhibitor with an IC50 of 85.8 μg/mL. Overall, against the six different evaluated cancerous cell lines, molecules 2, 10, and 11 were the most antiproliferative compounds. In silico predictions through docking point out 11, and ADME analysis to 11 and 12, as good candidates for being lead compounds for further derivations.

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Section: Molecular Dockingmentioning

confidence: 99%

In Vitro and In Silico Screening of 2,4,5-Trisubstituted Imidazole Derivatives as Potential Xanthine Oxidase and Acetylcholinesterase Inhibitors, Antioxidant, and Antiproliferative Agents

et al. 2020

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“…HER2 endows cancer cells with robust antioxidant properties [8,17]. Given the HNMT-HER2 interaction, we assessed the effect of TBHp-induced oxidative damage on NSCLC cells with HNMT knockdown.…”

Section: Discussionmentioning

confidence: 99%

HNMT Upregulation Induces Cancer Stem Cell Formation and Confers Protection against Oxidative Stress through Interaction with HER2 in Non-Small-Cell Lung Cancer

Kuo

Lin

Wang

et al. 2022

IJMS

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Background: The treatment of non-small-cell lung cancer (NSCLC) involves platinum-based chemotherapy. It is typically accompanied by chemoresistance resulting from antioxidant properties conferred by cancer stem cells (CSCs). Human epidermal growth factor receptor 2 (HER2) enhances CSCs and antioxidant properties in cancers, including NSCLC. Methods: Here, we elucidated the role of histamine N-methyltransferase (HNMT), a histamine metabolism enzyme significantly upregulated in NSCLC and coexpressed with HER2. HNMT expression in lung cancer tissues was determined using quantitative reverse transcription PCR (RT-qPCR). A publicly available dataset was used to determine HNMT’s potential as an NSCLC target molecule. Immunohistochemistry and coimmunoprecipitation were used to determine HNMT–HER2 correlations and interactions, respectively. HNMT shRNA and overexpression plasmids were used to explore HNMT functions in vitro and in vivo. We also examined miRNAs that may target HNMT and investigated HNMT/HER2′s role on NSCLC cells’ antioxidant properties. Finally, how HNMT loss affects NSCLC cells’ sensitivity to cisplatin was investigated. Results: HNMT was significantly upregulated in human NSCLC tissues, conferred a worse prognosis, and was coexpressed with HER2. HNMT depletion and overexpression respectively decreased and increased cell proliferation, colony formation, tumorsphere formation, and CSCs marker expression. Coimmunoprecipitation analysis indicated that HNMT directly interacts with HER2. TARGETSCAN analysis revealed that HNMT is a miR-223 and miR-3065-5p target. TBHp treatment increased HER2 expression, whereas shHNMT disrupted the Nuclear factor erythroid 2-related factor 2 (Nrf2)/ hemeoxygenase-1 (HO-1)/HER2 axis and increased reactive oxygen species accumulation in NSCLC cells. Finally, shHNMT sensitized H441 cells to cisplatin treatment in vitro and in vivo. Conclusions: Therefore, HNMT upregulation in NSCLC cells may upregulate HER2 expression, increasing tumorigenicity and chemoresistance through CSCs maintenance and antioxidant properties. This newly discovered regulatory axis may aid in retarding NSCLC progression and chemoresistance.

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“…These tridimensional structures were taken from PDB codes 3ERT [ 59 ], 4OAR [ 60 ], 2J6M [ 61 ], and 4DRH [ 62 ]. These structures were used as a target in previous computational works related with anticancer activity [ 63 , 64 , 65 ]. The receptors files were prepared in the graphic interface Auto-Dock Tools 1.4.5 (ADT) [ 56 ] where the water molecules were removed, and all hydrogens atoms were properly added, and nonpolar hydrogen were merged to carbon atoms.…”

Section: Methodsmentioning

confidence: 99%

Synthesis, Characterization, and Preliminary In Vitro Cytotoxic Evaluation of a Series of 2-Substituted Benzo [d] [1,3] Azoles

et al. 2021

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A series of benzo [d] [1,3] azoles 2-substituted with benzyl- and allyl-sulfanyl groups were synthesized, and their cytotoxic activities were in vitro evaluated against a panel of six human cancer cell lines. The results showed that compounds BTA-1 and BMZ-2 have the best inhibitory effects, compound BMZ-2 being comparable in some cases with the reference drug tamoxifen and exhibiting a low cytotoxic effect against healthy cells. In silico molecular coupling studies at the tamoxifen binding site of ERα and GPER receptors revealed affinity and the possible mode of interaction of both compounds BTA-1 and BMZ-2.

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EGFR, HER2 target based molecular docking analysis, in vitro screening of 2, 4, 5-trisubstituted imidazole derivatives as potential anti-oxidant and cytotoxic agents

Cited by 23 publications

References 65 publications

In Vitro and In Silico Screening of 2,4,5-Trisubstituted Imidazole Derivatives as Potential Xanthine Oxidase and Acetylcholinesterase Inhibitors, Antioxidant, and Antiproliferative Agents

In Vitro and In Silico Screening of 2,4,5-Trisubstituted Imidazole Derivatives as Potential Xanthine Oxidase and Acetylcholinesterase Inhibitors, Antioxidant, and Antiproliferative Agents

HNMT Upregulation Induces Cancer Stem Cell Formation and Confers Protection against Oxidative Stress through Interaction with HER2 in Non-Small-Cell Lung Cancer

Synthesis, Characterization, and Preliminary In Vitro Cytotoxic Evaluation of a Series of 2-Substituted Benzo [d] [1,3] Azoles

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