Rahiminezhad Arezo, Moghadam Mahboube Eslami, Divsalar Adeleh, Mesbah A Wahid
Chemistry & Chemical Engineering Research Center of Iran, Tehran, Iran.
Department of Cell & Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
J Mol Model. 2021 Dec 7;28(1):2. doi: 10.1007/s00894-021-04984-x.
Cisplatin is a widely used anti-cancer drug which inhibits the replication and polymerization of DNA molecule while showing some side effects and drug resistance. For this reason, to enhance its therapeutic index, researchers have synthesized several thousand analogs and tested their properties. In this project, several cisplatin analogs were designed to theoretically study the biological activity and lipophilicity effects on amine changes. The amines of the cisplatin molecule were substituted with aliphatic amines in different analogs. Computational methods such as molecular dynamics simulation, molecular docking, and molecular mechanics Poisson-Boltzmann surface area analysis were performed to investigate the binding of six cisplatin derivatives with DNA. The binding affinity and potential interactions of these drugs with double-strand DNA were analyzed. The stability effect of these drugs was investigated via root-mean-square deviation and root-mean-square fluctuation analysis, which showed that some analogs can break base-pair interaction at the end of DNA and reduced the stability of DNA. Also, the results revealed that the hydrogen bond is one of the most important factors in the binding of cisplatin's adduct to DNA. Molecular mechanics Poisson-Boltzmann surface area analysis indicated that electrostatic and van der Waals interactions are the most important deriving forces to the binding of cisplatin's drug to DNA. Finally, data revealed that cisplatin and the cis-dichloro-dimethylamine-platin tendency for binding to DNA are greater than that of other analogs.
顺铂是一种广泛使用的抗癌药物，它能抑制DNA分子的复制和聚合，但同时也会产生一些副作用和耐药性。因此，为了提高其治疗指数，研究人员合成了数千种类似物并测试了它们的性质。在这个项目中，设计了几种顺铂类似物，从理论上研究胺基变化对生物活性和亲脂性的影响。在不同的类似物中，用脂肪胺取代了顺铂分子的胺基。采用分子动力学模拟、分子对接和分子力学泊松-玻尔兹曼表面积分析等计算方法，研究了六种顺铂衍生物与DNA的结合情况。分析了这些药物与双链DNA的结合亲和力和潜在相互作用。通过均方根偏差和均方根波动分析研究了这些药物的稳定性影响，结果表明一些类似物可以破坏DNA末端的碱基对相互作用，降低DNA的稳定性。此外，结果还表明氢键是顺铂加合物与DNA结合的最重要因素之一。分子力学泊松-玻尔兹曼表面积分析表明，静电相互作用和范德华相互作用是顺铂药物与DNA结合的最重要驱动力。最后，数据显示顺铂和顺二氯二甲基胺铂与DNA结合的倾向大于其他类似物。
