基于QSAR模型、紫外光谱法和分子对接技术研究杂质5-羟甲基糠醛及其二聚体和代谢产物与DNA的相互作用  

Study on the interaction between DNA and impurities 5-hydroxymethylfurfural and its dipolymer and metabolite using QSAR model,ultraviolet spectroscopy and molecular docking technique

作　　者：林铌 张佳宁 刘丽[1] 靳洪涛[2,3] 王三龙 刘颖[1] LIN Ni;ZHANG Jia-ning;LIU Li;JIN Hong-tao;WANG San-long;LIU Ying(Key Laboratory of Beijing for Nonclinical Safety Evaluation Research of Drugs,National Center for Safety Evaluation of Drugs,National Institutes for Food and Drug Control,Beijing 100176,China;New Drug Safety Evaluation Center,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China;Beijing Union-Genius Pharmaceutical Technology Development Co.,Ltd.,Beijing 100176,China)

机构地区：[1]中国食品药品检定研究院、国家药物安全评价监测中心、药物非临床安全评价研究北京市重点实验室,北京100176 [2]中国医学科学院药物研究所新药安全评价研究中心,北京100050 [3]北京协和建昊医药技术开发有限责任公司,北京100176

出　　处：《药物分析杂志》2023年第7期1221-1228,共8页Chinese Journal of Pharmaceutical Analysis

基　　金：中国食品药品检定研究院关键技术研究基金(GJJS-2022-9-1);中国食品药品检定研究院中青年发展研究基金(2022C1)。

摘　　要：目的:研究杂质单体5-羟甲基糠醛(5-hydroxymethylfurfural, 5-HMF)及其二聚体5,5’-二甲酰基呋喃二甲醚[5,5’-oxydimethylenebis(2-furfural),OMBF]、单体代谢产物5-磺基氧甲基糠醛(5-sulfooxymethylfurfural, 5-SMF)与DNA的相互作用方式,为3种杂质潜在的DNA损伤风险和遗传毒性机制研究提供理论基础。方法:采用QSAR模型预测5-HMF、OMBF和5-SMF与DNA结合的可能性及遗传毒性警示结构,然后采用紫外光谱法对3种杂质与小牛胸腺DNA(ctDNA)相互作用后的光谱学变化评估可能的作用方式,最后用分子对接技术将3种杂质与双链DNA分子模拟对接,直观地呈现三者与DNA的作用方式,并比较3种杂质与DNA结合的稳定性。结果:4种QSAR模型预测结果提示5-HMF、OMBF和5-SMF 3种杂质均可能与DNA结合,且均具有潜在致突变或致癌性。5-HMF、OMBF和5-SMF均能使ctDNA的紫外吸收光谱发生减色效应(减色程度分别为8.2%、22.6%和8.7%)和蓝移(位移距离分别为1.2、3.5和1.0 nm),说明3种杂质均可能以小沟槽结合的方式与ctDNA发生相互作用,且均可能与碱基对发生π-π相互作用。通过分子对接模拟验证了3种杂质与DNA均可能发生小沟槽结合,并与碱基对产生氢键作用,OMBF和5-SMF还可能与碱基发生π-π相互作用。通过比较杂质小分子与DNA的平均结合能,结果证明OMBF最强,5-SMF次之,5-HMF最弱。结论:3种杂质均可能与DNA分子相互作用产生范德华力(小沟槽结合方式)、氢键和π-π相互作用,且均可能与DNA以非共价结合方式形成杂质-DNA复合物,从而对DNA结构造成一定的损伤。本研究从分子水平对5-HMF、OMBF和5-SMF与DNA可能的相互作用方式及其潜在致DNA损伤和遗传毒性的机制进行了探索性研究,为杂质小分子的遗传毒性研究提供了新思路。Objective:To study the interaction between DNA and impurities 5-hydroxymethylfurfural(5-HMF),its dipolymer 5,5'-oxydimethylenebis(2-furfural)(OMBF),and its metabolite 5-sulfooxymethylfurfural(5-SMF),and to provide theoretical basis to the research of the mechanism of potential risk of DNA damage and genotoxicity.Methods:The possibility of DNA binding and its warning structure of genotoxic of 5-HMF,OMBF and 5-SMF were predicted by using QSAR models,then the interaction between the three impurities and calf thymus DNA(ctDNA)was determined by using an ultraviolet(UV)spectroscopy to evaluate the possible mode of action for the spectral changes,and the simulated docking of three impurities and double-stranded DNA were finally investigated by using a computational molecular docking technology,the interaction between the three impuirities and DNA was intuitively presented,and the stability of the binding of three impurities and DNA were compared.Results:The results predicted by four QSAR models showed that all three impurities had the ability to bind with DNA(structural alert:furan)and the plausibility to induce mutagenicity and carcinogenicity(structural alert:aldehyde).5-HMF,OMBF and 5-SMF showed a hypochromic effect on the UV spectrum of ctDNA with the degree of 8.2%,22.6%and 8.7%,respectively,and blue shift with distance of 1.2 nm,3.5 nm,and 1.O nm.It demonstrated that three impurities could interact with ctDNA in the form of minor groove binding,accompanied by a-interaction with base pairs.The results obtained from computer-aided molecular docking simulation illustrated that three impurities could bind in the minor groove of DNA,hydrogen bonds with the base pairs,and the T-interaction with the base pairs were found on OMBF and 5-SMF.By comparing the average of interaction energies of small impurities and DNA indicated that OMBF was the strongest,and then was the 5-SMF and 5-HMF was the weakest.Conclusion:The above results show that,the three impurities are capable to interact with DNA to form produce van der Waals

关 键 词：5-羟甲基糠醛 5 5’-二甲酰基呋喃二甲醚 5-磺基氧甲基糠醛 DNA 定量构效关系 分子对接 紫外光谱法 

分 类 号：R917[医药卫生—药物分析学]