铁皮石斛中菲类化合物反应性与药代动力学计算

Calculation of the phenanthrene reactivity and pharmacodynamics in Dendrobium officinale

目的:比较分析铁皮石斛中菲类化合物的结构特征、谱学性质、反应活性和药代动力学性质,为新药开发提供参考。方法:采用密度泛函理论ωB97XD/6-311+G(d, p)方法计算研究铁皮石斛中12种菲类化合物结构与性质,并分析分子表面静电势、全局和局部反应性描述符,预测反应活性,同时借助ACD/Labs percepta平台预测其成药性和药代动力学参数。结果:12种菲类化合物具有较好的溶剂稳定性。紫外-可见光谱理论计算值与实验数据吻合较好。发现反应活性顺序是菲醌型>菲型>二氢菲型,而各个化合物的活性位点是化合物1~8(菲型),C9与C10反应活性最高;化合物9(菲醌型)酮基上的O反应活性最高;化合物10、11、12(二氢菲型)连接供电子基团的C2与C7反应性强;12种化合物中-OH(O)易发生亲电反应。药代动力学分析显示12种菲类化合物均符合Lipinski类药性原则,被动扩散能力佳,血浆蛋白结合能力强。化合物6、7、8在小肠内吸收一般、不易透过血脑屏障,对肝药酶基本无抑制作用。12种菲类化合物中,化合物6、7、8、9、12无心脏毒性。结论:计算研究可揭示铁皮石斛中菲类化合物的构效关系,阐明其活性作用部位,为结构改造和药代动力学实验研究提供理论支持。

Objective: To investigate the structural characteristics, spectral properties, reactivity, and pharmacodynamic properties of phenanthrenes in Dendrobium officinale using density functional theory combined with ACD/Labs percepta platform. Methods: The structure and spectral properties of 12 phenanthrene compounds in Dendrobium officinale were calculated at the level of ωB97XD/6-311+G(d, p) in the density functional theory.The reactivity including molecular surface electrostatic potential, global and local reactivity descriptors were calculated. And then the pharmacodynamic parameters were predicted by ACD/labs percepta platform. Results:12 phenanthrenes had good solvent stability. The theoretical value of UV-Vis spectra agrees well with the experimental data. The reactivity order of 12 phenanthrene compounds is phenanthrene quinone > phenanthr ene>dihydrophenanthrene. The reaction site of each compound was compared: compounds 1-8(phenanthrene type), C9 and C10 had the highest reaction activity;compound 9(phenquinone type) had the highest reaction activity on ketone group. Compounds 10, 11, 12(dihydrophenanthrene type) had strong reactivity with C2 and C7 linked to the electron-donating group. Among the 12 compounds,-OH(O) was prone to electrophilic reaction.Pharmacodynamics analysis showed that all the 12 phenanthrenes were in line with Lipinski pharmacological principle, with good passive diffusion ability and strong plasma protein binding ability, and might have slight genotoxicity. Compounds 6, 7, 8 were moderately absorbed in the small intestine, which did not easily penetrate the blood-brain barrier and hardly had inhibitory effect on liver drug enzymes. Compounds 6, 7, 8, 9 and 12 had no cardiotoxicity. Conclusion: Theoretical investigation revealed the structure-activity relationship of phenanthrenes in Dendrobium officinale and elucidated their active sites, which provides theoretical support for subsequent structural modification and pharmacokinetic studies.