Identification of Potential Inhibitors against Epstein–Barr Virus Nuclear Antigen 1 (EBNA1): An Insight from Docking and Molecular Dynamic Simulations

3区 · 医学

Article

作者: Jha, Hem Chandra ; Kar, Parimal ; Jonniya, Nisha Amarnath ; Jakhmola, Shweta ; Sk, Md Fulbabu ; Rani, Annu

Epstein-Barr virus (EBV), a known tumorigenic virus, is associated with various neuropathies, including multiple sclerosis (MS). However, there is no anti-EBV FDA-approved drug available in the market. Our study targeted EBV protein EBV nuclear antigen 1 (EBNA1), crucial in virus replication and expressed in all the stages of viral latencies. This dimeric protein binds to an 18 bp palindromic DNA sequence and initiates the process of viral replication. We chose phytochemicals and FDA-approved MS drugs based on literature survey followed by their evaluation efficacies as anti-EBNA1 molecules. Molecular docking revealed FDA drugs ozanimod, siponimod, teriflunomide, and phytochemicals; emodin; protoapigenone; and EGCG bound to EBNA1 with high affinities. ADMET and Lipinski's rule analysis of the phytochemicals predicted favorable druggability. We supported our assessments of pocket druggability with molecular dynamics simulations and binding affinity predictions by the molecular mechanics generalized Born surface area (MM/GBSA) method. Our results establish a stable binding for siponimod and ozanimod with EBNA1 mainly via van der Waals interactions. We identified hot spot residues like I481', K477', L582', and K586' in the binding of ligands. In particular, K477' at the amino terminal of EBNA1 is known to establish interaction with two bases at the major groove of the DNA. Siponimod bound to EBNA1 engaging K477', thus plausibly making it unavailable for DNA interaction. Computational alanine scanning further supported the significant roles of K477', I481', and K586' in the binding of ligands with EBNA1. Conclusively, the compounds showed promising results to be used against EBNA1.

2020-11-01·Life Sciences3区 · 医学

Protoflavones in melanoma therapy: Prooxidant and pro-senescence effect of protoapigenone and its synthetic alkyl derivative in A375 cells

3区 · 医学

Article

作者: Csekes, Erika ; Račková, Lucia ; Vágvölgyi, Máté ; Hunyadi, Attila

AIMSIn our study, the anticancer effects of a semisynthetic p-quinol, protoapigenone 1'-O-butyl ether (PABut), were tested in human melanoma A375 cells also in comparison with natural congener, protoapigenone (PA).MAIN METHODSThe cytotoxic effect of PABut and PA was determined using MTT assay. Flow cytometry analysis was used to evaluate the influence of the compounds tested on ROS generation and cell cycle distribution in A375 cells. Moreover, apoptosis was evaluated by AO/EB dual staining as well as by flow cytometry. Markers of senescence were quantified by spectrofluorimetry and by Western blot analysis.KEY FINDINGSBoth PABut and PA showed significant cytotoxicity against melanoma A375 cells at sub-micromolar concentrations. Both protoflavones induced comparable cell cycle arrest in G2/M phase. However, a more profound upregulation of intracellular ROS levels was found following PABut treatment. An increased apoptosis in the cells following 48 h treatment with both protoflavones tested was also confirmed. Both compounds tested remarkably upregulated p21 protein levels in A375 cells. Unlike PA, PABut significantly decreased protein levels of NAD⁺-dependent deacetylase SirT1 and β-actin accompanied by mild significant upregulation of mitochondrial SOD2 and senescence markers, p16 protein and SA-β-Gal activity. However, a significant upregulation of p53 only following PA treatment was found.SIGNIFICANCEThese results suggest that PABut and PA confer high chemotherapeutic potential in melanoma cells and are suitable for further testing. Furthermore, modification of protoapigenone with 1'-O-butyl ether moiety can be associated with improved senescence-inducing effect and, thus, enhanced chemotherapeutic potency of PABut compared to the unmodified natural protoflavone.

2020-09-01·Toxicology and Applied Pharmacology3区 · 医学

The protoapigenone analog WYC0209 targets CD133+ cells: A potential adjuvant agent against cancer stem cells in urothelial cancer therapy

3区 · 医学

Article

作者: Wu, Wen-Jeng ; Kung, Mei-Lang ; Wei, Yu-Ching ; Yang, Juan-Cheng ; Wu, Yang-Chang ; Li, Ching-Chia ; Yeh, Bi-Wen ; Lee, Hsueh-Te ; Li, Wei-Ming ; Yu, Liang-En

Urothelial carcinoma (UC) is one of the highest incidence cancers that rank the fourth commonly diagnosed tumors worldwide. The unresectable lesions that are resistant to therapeutic interventions is the major cause leading to death. Previous studies had shown that the resistance and metastatic consequence may arise from cancer stem-like cells population. The phytochemical flavonoids have promised bioactivity and potent anti-carcinogenic effects, and trap great attentions for cancer chemoprevention and/or adjuvant chemotherapy. However, the mechanisms of flavonoids on cancer stemness is still obscured. In this study, we analyzed the biofunctional effects of as-prepared flavonoid derivative-WYC0209 on T24, BFTC905 and BFTC909 human UC cell lines. Our results demonstrated that WYC0209 significantly induced anti-cell viability on UC cells through decreased Akt/NFkB signaling. Moreover, WYC0209 enhanced the cell apoptosis through activated the caspase-3 activity and inactivated Bcl-xL expression. Interestingly, WYC0209 dramatically inhibited the cancer stem cells (CSCs) traits, including attenuation of side population and tumorsphere formation in which were through declined EMT-CSCs markers including MDR1, ABCG2 and BMI-1. We further validated the effects of WYC0209 on several CSC surface markers including CD133, CD44, SOX-2 and Nanog. Our results showed that WYC0209 markedly inhibited CD133 expressions in both transcriptional and translational levels. High expression levels of CD133 was also demonstrated in human upper tract UC specimens. In summary, our study showed that WYC0209 may potentially as an adjuvant agent to against CD133-driven UC CSCs and provide a beneficial strategy to against UC cancer therapeutics resistant.

100 项与 RY-10-4 相关的药物交易

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