癌癥是人類致死的原因之一,。高效特異的治癌藥物設計與合成是學術(shù)界公認的科研熱點和難點。近日,，美國化學學會屬下的知名雜志Journal of Chemical Information and Modeling以封面文章推出了高效特異性識別與抑制癌細胞的多肽分子新藥物,。這是研究生院化學與化工學院博士生崔巍同學與其導師計明娟教授等人通過計算機輔助設計完成的重要研究成果。
文章提出,，G3BP是在很多腫瘤細胞中高表達的一種蛋白質(zhì)分子,，圍繞該蛋白尋找特異性抗腫瘤藥物是重要治療手段之一。
他們應用分子動力學模擬方法,，從理論上分析了涉及G3BP的蛋白質(zhì)相互作用,，并依據(jù)獲取的Ras-GAP蛋白與G3BP蛋白質(zhì)識別的重要信息設計合成了兩條全新序列的抗腫瘤多肽分子。細胞實驗表明,，這兩條多肽不僅可以增強腫瘤細胞對順鉑等傳統(tǒng)抗腫瘤藥物的敏感性,，而且多肽本身對腫瘤細胞也有顯著的抑制作用，其藥理活性顯著高于國際上其他研究人員此前已報道的多肽分子,。更重要的是,，該研究成果設計合成的抗腫瘤多肽藥物分子對腫瘤細胞顯示出很高的特異性，并對正常細胞的毒性遠低于同劑量的順鉑藥物,。
該工作對進一步研發(fā)全新機理的特異靶向性抗腫瘤新藥提供了理論和實驗依據(jù),，具有重要的學術(shù)意義和應用價值。(生物谷Bioon.com)
生物谷推薦原文出處：
J. Chem. Inf. Model. DOI: 10.1021/ci900404p
Structure-Based Design of Peptides against G3BP with Cytotoxicity on Tumor Cells
Wei Cui?, Zhuo Wei?, Quan Chen?, Yuanhua Cheng, Lingling Geng§, Jian Zhang§, Jianhua Chen*§, Tingjun Hou*? and Mingjuan Ji*?
Herein, we report a successful application of molecular modeling techniques to design two novel peptides with cytotoxicity on tumor cells. First, the interactions between the nuclear transport factor 2 (NTF2)-like domain of G3BP and the SH3 domain of RasGAP were studied by a well-designed protocol, which combines homology modeling, protein/protein docking, molecular dynamics simulations, molecular mechanics/generalized born surface area (MM/GBSA) free energy calculations, and MM/GBSA free energy decomposition analysis together. Then, based on the theoretical predictions, two novel peptides were designed and synthesized for biological assays, and they showed an obvious sensitizing effect on cis-platin. Furthermore, the deigned peptides had no significant effects on normal cells, while cis-platin did. Our results demonstrate that it is feasible to use the peptides to enhance the efficacy of clinical drugs and to kill cancer cells selectively. We believe that our work should be very useful for finding new therapies for cancers.
