β受体阻断剂的理化性质与药动学参数模型建立及其在预测药物吸收中的应用
首发时间:2013-01-10
摘要:目的: 建立β受体阻断剂的理化性质参数与其在人体内的药动学过程的数学模型,对β受体阻断剂进行结构改造、优化和发现新的化合物实体,为新药早期筛选提供科学依据。方法: 首先采用分子模拟的方法,应用分子力学和分子动力学程序对β受体阻断剂的立体结构进行能量优化, 获得能量最低,最稳定的结构;其次采用HyperChem软件计算模拟得到的稳定结构的理化性质参数,如油水分配系数(Log P)、表面积(Surface Area)等;最后建立理化性质参数与药物动力学参数之间的模型,并进行可行性验证。结果: β受体阻断剂的模拟理化性质参数与在体药代动力学参数存在相关性,验证结果表明可行。结论: 建立的模型可用于预测新的β受体阻断剂的吸收,对该类药物的进一步结构改造和全新结构设计具有重要的指导意义。
关键词: 药物动力学 分子力学和分子动力学 分子模拟 β受体阻断剂
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The correlation between the physicochemical properties and the pharmacokinetic parameters and its application in the prediction of drug absorption for β-Receptor blockers
Abstract:Objective: To establish the correlation between the physicochemical properties and the pharmacokinetic parameters for β-receptor blockers, in order to modifine and optimize the structures, to discover the new molecular entities, and to provide scientific basis for new drug screening. METHODS: The structures of β-receptor blockers were conversed from two to three dimensional structure by InsightⅡProgram. The conversed structures were optimized to the minimum energy by the steepest descent and conjugate gradient methods. The physicochemical properties of the optimized structures, including Log P and surface area et al, were calculated by HyperChem Program. The interrelation between the physicochemical properties and pharmacokinetic parameters for β-receptor blockers was analyzed. RESULTS: There was a good correlation between the hydrophobicity constants ( Log P) and the reached peak time ( Tmax ) after extravenous administration of β-receptor blockers to the subjects. CONCLUSION: The correlation between the physicochemical properties and its pharmacokinetic parameters can provide instructions to new drug design for β-receptor blockers.
Keywords: Pharmacokinetics Molecular mechanics and dynamics Molecular simulation β-receptor blockers
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β受体阻断剂的理化性质与药动学参数模型建立及其在预测药物吸收中的应用
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