【作者】 刘伟；

【导师】 李洪林；

【作者基本信息】 华东理工大学 ， 药学， 2015， 硕士

【摘要】 药代动力学是新药临床前研究的重要内容,也是药物临床研究中失败的主要原因之一。随着计算机辅助药物设计的快速发展和临床前药动学数据的不断积累,采用计算的方法来预测药动学参数为新药的临床前优化提供了新的策略。本文首先介绍了药代动力学的基本概念和理论预测的基本原理,并对药代动力学预测的难点之一——药物口服生物利用度的预测进行了概述,指出了现有药物口服生物利用度预测模型的不足之处,比如数据集质量问题、变量选择问题以及模型的预测准确性问题。针对上述问题,我们采用方差分析和理想化函数方法构建了定量预测口服生物利用度的模型。本文以汤森路透数据库中收集的药物口服生物利用度数据集为参考,通过方差分析选择对口服生物利用度有显著影响的描述符,并用热图进行进一步验证,随后采用理想化函数将上述描述符进行表征和归一化,并采用Shannon计算每个描述符的权重,最终构建了定量预测口服生物利用度模型。此外,我们选择已报道的两个外部数据集(Moda和Hou数据集)作为测试集,对本文设计的方法进行评价。结果表明：对于Moda测试集,Moda的HQSAR模型的预测结果为R2=0.7681,而本研究中设计的QEB方法的预测结果为R2=0.8218；对于Hou数据集,Hou的GFA模型的预测结果为R2=0.71,而本研究中设计的QEB方法的预测结果为R2=0.7936。本文中采用的定量预测口服生物利用度方法预测准确性要高于现有的其它预测模型,这为药物口服生物利用度预测方法的进一步研究和发展提供了理论依据。FTase是一种的金属蛋白酶,它对于Ras蛋白的生物功能的正常发挥起着重要的作用。本课题组的前期的研究中,通过虚拟筛选得到了一批结构新颖的FTase抑制剂。本文针对其中1,3-噻唑-4烷酮类先导1a (IC50=5.14 μM),采用金属特异性对接软件(MPSDock),预测其与FTase (PDB编号：1LD8)的结合模式,提出该类化合物的结构改造策略,并通过生物活性测试,得到了活性较高的化合物1e和1f,它们对FTase的半数有效抑制浓度分别为0.063μM和0.068μM。更多还原

【Abstract】 Pharmacokinetic is an important part of pre-clinical drug optimization, which is also the main reasons for attrition in the drug development. With the rapid development of computer aided drug design and the steady accumulation of preclinical pharmacokinetic data, researchers use computational method to predict the pharmacokinetic parameters for new drug preclinical optimization. Firstly, we have introduced the basic concept of pharmacokinetic and the basic principle of theory. Meanwhile, some shortages and limitations in the present oral bioavailability prediction methods have emerged, such as poor quality of the collected dataset, how to select variables and poor accuracy of methods. Among them, how to select variables and establishment of high precision of prediction models are the most intractable issues of developing an oral bioavailability method. In the context, we analyzed the variance and desirability function to construct quantitative evaluation of oral bioavailability (QEB).In this context, taking oral bioavailability dataset which belong to Thomson Reuters Integrity datasets as the reference criterion, the thesis performed variance analysis to study the effect of independent variables on the dependent variable, and uses heatmap to verify descriptors which were collected by variance analysis, furthermore, we employ desirable functions to characterize and normalize the independent variables and uses shannon entropy to calculate the weight of each descriptor. In addition, we selected two external datasets (Moda test sets and Hou test sets) which had been reported as two test sets and performed evaluation of quantitative evaluation of oral bioavailability (QEB). For the Moda test sets, the result of HQSAR model is R2=0.7681 while the result of our model (QEB) is R2=0.821. For the Hou test sets, the result of GFA model is R2=0.71 while the result of our model (QEB) is R2=0.793.The result indicated that QEB had an obvious advantage for predicting oral bioavailability over other methods. Moreover, QEB method provided a new strategy for the development of oral bioavailability prediction method.Farnesyltransferase (FTase) is a zinc metalloenzyme found in a diversity of organisms, which plays a vital role in regulating the biological functions of Ras protein. Through virtual screening, a series of hits with high inhibitory activity against FTase were previously discovered in our group.In the paper, focusing on lead compound la (IC50=5.14±0.0071 μM), we performed structure-activity relationship (SAR) analysis on the potential binding poses, which were obtained by utilizing metal docking program (MPSDock). Based on the SAR analysis, we proposed a structural optimization strategy. According to chemical synthesis and biological activity assays, compound le showed an IC50 value of 0.063 μM and compound 1f showed an IC50 value of 0.068 μM.更多还原