Method Development Of Oral Bioavailability Of Drug Prediction And SAR Of 1,3-thiazolidin-4-one As Ftase Inhibitors

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.