Pharmacokinetic predictions of ROS-mediated targets and genotoxin combinations via multiple ligand simultaneous docking and ROS evaluation in vitro using HepG2 cell lines.

IF 2.6 4区 生物学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
3 Biotech Pub Date : 2024-11-01 Epub Date: 2024-10-14 DOI:10.1007/s13205-024-04109-0
C P Sri Snehaa, Praveen Kumar Issac, Palanisamy Rajaguru, Velan Pugalenthi
{"title":"Pharmacokinetic predictions of ROS-mediated targets and genotoxin combinations via multiple ligand simultaneous docking and ROS evaluation in vitro using HepG2 cell lines.","authors":"C P Sri Snehaa, Praveen Kumar Issac, Palanisamy Rajaguru, Velan Pugalenthi","doi":"10.1007/s13205-024-04109-0","DOIUrl":null,"url":null,"abstract":"<p><p>Although combination therapy is known for its high efficacy, reduced side effects and drug resistance, toxicity remains a major drawback. Some of the genes are likely to induce hepatotoxicity through ROS-mediated mechanisms when a drug is metabolized alone or in combination in the liver. To address this, we have developed a scientific approach to predict the toxicity of different genotoxin combinations and validate their interactions with various targets. The current study is an extensive study of our previous set of in vivo rat liver microarray data processed using R studio for their functional analysis. About five combinations of genotoxins such as CPT/ETP, CPT/CPL, ETP/CPL, CP/CPT and EES/CP along with their differential gene expression targeting Chemical carcinogenesis-ROS are chosen for this study. We aim to examine the binding affinity of different genotoxin combinations using in silico multiple ligand simultaneous docking (MLSD) and are then bio-evaluated for cytotoxicity in vitro using human hepatocellular carcinoma cell lines (HepG2) with the MTT assay. As a result, dose-response cytotoxicity with its strength of interactions and a significant variance in ROS levels in the treated cells is observed compared to their IC<sub>50</sub> values. Out of 5 combinations such as CPT/CPL, ETP/CPL and EES/CP are found not only to be significantly cytotoxic but also induce oxidative stress specifically above their IC<sub>50</sub> values with good and moderate binding interactions ensuring their toxicity. On the contrary, the safe combinations are found to be CTP/ETP and CP/CPT possibly with no and tolerable adverse effects standing as preliminary information for researchers in drug design and development.</p>","PeriodicalId":7067,"journal":{"name":"3 Biotech","volume":null,"pages":null},"PeriodicalIF":2.6000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471743/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"3 Biotech","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.1007/s13205-024-04109-0","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/14 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Although combination therapy is known for its high efficacy, reduced side effects and drug resistance, toxicity remains a major drawback. Some of the genes are likely to induce hepatotoxicity through ROS-mediated mechanisms when a drug is metabolized alone or in combination in the liver. To address this, we have developed a scientific approach to predict the toxicity of different genotoxin combinations and validate their interactions with various targets. The current study is an extensive study of our previous set of in vivo rat liver microarray data processed using R studio for their functional analysis. About five combinations of genotoxins such as CPT/ETP, CPT/CPL, ETP/CPL, CP/CPT and EES/CP along with their differential gene expression targeting Chemical carcinogenesis-ROS are chosen for this study. We aim to examine the binding affinity of different genotoxin combinations using in silico multiple ligand simultaneous docking (MLSD) and are then bio-evaluated for cytotoxicity in vitro using human hepatocellular carcinoma cell lines (HepG2) with the MTT assay. As a result, dose-response cytotoxicity with its strength of interactions and a significant variance in ROS levels in the treated cells is observed compared to their IC50 values. Out of 5 combinations such as CPT/CPL, ETP/CPL and EES/CP are found not only to be significantly cytotoxic but also induce oxidative stress specifically above their IC50 values with good and moderate binding interactions ensuring their toxicity. On the contrary, the safe combinations are found to be CTP/ETP and CP/CPT possibly with no and tolerable adverse effects standing as preliminary information for researchers in drug design and development.

利用 HepG2 细胞系,通过多配体同时对接和 ROS 体外评估,对 ROS 介导的靶标和基因毒素组合进行药代动力学预测。
尽管联合疗法以疗效高、副作用小和耐药性低而著称,但毒性仍然是其主要缺点。当药物在肝脏中单独或联合代谢时,其中一些基因很可能通过 ROS 介导的机制诱发肝毒性。为此,我们开发了一种科学方法来预测不同基因毒素组合的毒性,并验证它们与各种靶点的相互作用。目前的研究是对我们之前使用 R studio 处理的一组体内大鼠肝脏微阵列数据进行功能分析的广泛研究。本研究选择了五种基因毒素组合,如 CPT/ETP、CPT/CPL、ETP/CPL、CP/CPT 和 EES/CP,以及它们针对化学癌变-ROS 的不同基因表达。我们的目的是利用硅学多配体同时对接(MLSD)技术研究不同基因毒素组合的结合亲和力,然后使用 MTT 法对人肝癌细胞株(HepG2)进行体外细胞毒性生物评估。结果,观察到剂量-反应细胞毒性及其相互作用的强度,以及与它们的 IC50 值相比,处理细胞中 ROS 水平的显著差异。在 CPT/CPL、ETP/CPL 和 EES/CP 等 5 种组合中,发现它们不仅具有显著的细胞毒性,而且还能诱导氧化应激,其毒性明显高于其 IC50 值,其良好和适度的结合相互作用确保了它们的毒性。相反,CTP/ETP 和 CP/CPT 被认为是安全的组合,它们可能不会产生任何不良影响,而且是可以承受的,这为研究人员进行药物设计和开发提供了初步信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
3 Biotech
3 Biotech Agricultural and Biological Sciences-Agricultural and Biological Sciences (miscellaneous)
CiteScore
6.00
自引率
0.00%
发文量
314
期刊介绍: 3 Biotech publishes the results of the latest research related to the study and application of biotechnology to: - Medicine and Biomedical Sciences - Agriculture - The Environment The focus on these three technology sectors recognizes that complete Biotechnology applications often require a combination of techniques. 3 Biotech not only presents the latest developments in biotechnology but also addresses the problems and benefits of integrating a variety of techniques for a particular application. 3 Biotech will appeal to scientists and engineers in both academia and industry focused on the safe and efficient application of Biotechnology to Medicine, Agriculture and the Environment.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信