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目的:通过优化靶向蛋白激酶C-αmRNA的反义设计,获得优于阳性药ISIS3521的反义药物。方法:RNAstructure预测靶mRNA二级结构,针对二级结构单元设计。体外评价药物对A549细胞增殖的抑制效应。SPSS进行构效关系(QSAR)分析。结果:29个反义药物中3个IC_(50)值显著低于ISIS3521。靶二级结构单元膨胀环、内环、结点的碱基数、药物结构自由能和反应自由能在QSAR方程中有统计意义。多元回归R=0.68,P=0.0193。2个S-ODN有良好的靶结构与自由能但药效差。结论:计算机辅助药物设计有助于获得体外药效优于ISIS3521的反义药物。靶二级结构单元的不稳定程度和自由能影响药效。影响药效的其它因素则有待进一步研究。
OBJECTIVE: By optimizing the antisense design targeting protein kinase C-α mRNA, antisense drugs superior to the positive drug ISIS3521 were obtained. Methods: RNAstructure predicted target mRNA secondary structure, targeting secondary structure unit design. In vitro evaluation of drugs on A549 cell proliferation inhibitory effect. SPSS QSAR analysis. Results: Three IC 50 values of 29 antisense drugs were significantly lower than those of ISIS3521. Target secondary structure unit expansion ring, the inner ring, the number of nodes, drug free energy and free energy in the QSAR equation was statistically significant. Multiple regression R = 0.68, P = 0.0193.2 S-ODN has good target structure and free energy but poor efficacy. CONCLUSION: Computer-aided drug design helps to obtain antisense drugs with superior in vitro potency over ISIS3521. The degree of instability and free energy of the target secondary structure units affect the efficacy. Other factors that affect efficacy are for further study.