Pinacidil 的硫脲／氰胍类似物降压活性的定量构效关系研究
QSAR Study on Hypotensive Activity of Analogues of Pinacidil
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摘要: 以POLYGEN软件包中的CHARMm程序和集团坐标轮换法对合成的15个pinacidil类似物及副产物的结构进行计算机分子模拟,分别以MM2法和CDNO/2法计算了上述化合物的11个分子力学和13个量子化学结构参数,将所得的结构参数与化合物的血管舒张活性进行相关分析,以逐步回归分析建立了两个相关性较好的方程。lg1/IC50(1)=-0.1259+1.711DM+0.0930PS(n=16,R=0.7444;S=1.3121,F=8.0771>F2,13(α≤0.01)=6.70);lg1/IC50(2)=1.2114- 28.7840QN(1) +0.1265DM (n=16,R=0.7658,S=0.4616,F=9.2182>F2,13 (α≤0.01) =6.70)。结果表明,化合物的血管扩张活性随分子偶极矩(DM)、分子的溶剂可及疏水性表面积与亲水性表面积的比值(PS)、吡啶基氮原子电荷的绝对值QN(1)的增大而增大,化合物的血管扩张活性主要取决于分子的电荷分布和分子的疏水性。Abstract: 11 molecular mechanics(MM)parameters and 13 quantum chemical parameters of Pinacidil-type cyanoguanidine, thioureas and imine-derivated compounds were calculated by MM2 method and CNDO/2 method respectively. Two significant correlation equations between the vasodilator activity of these compounds and the structural parameters mentioned above were established by stepwise regression analyses. lg1/IC50(1)=0.1259+1.7111DM+0.0930PSn=16,R=0.7444,S=1.3121,F=8.0771>F2,13(α≤0.01)=6.70;lg1/IC50(2)=1.2114-28.7840QN(1)+0.1265DM(n=16,R=0.7658,S=0.4616,F=9.2182>F2,13(α≤0.01)=6.7. The QSAR equations show that the vasodilator activity of these compounds increases with the increase of dipolemoment(DM) , ratiovalue(PS) of solvent-accessible hydrophobicsurface area of molecule to the hydrophilic, and of absolute value of electronic charge of pyridinenitrogen. The results also suggest that the vasodila to ractivity of these compounds is mainly dependent upon the distribution of electronic charge and the hydrophobicity of molecules.
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