Dissertation > Excellent graduate degree dissertation topics show

Investigate the P-glycoprotein Modulators and Androgen Receptor Antagonists Base on the Computer Aided Drug Design Methods

Author: WuJianHua
Tutor: ZhaoChunYan
School: Lanzhou University
Course: Medicinal Chemistry
Keywords: Resistance QSAR Flexible Docking P-glycoprotein Androgen receptor
CLC: R96
Type: Master's thesis
Year: 2011
Downloads: 74
Quote: 0
Read: Download Dissertation

Abstract

Resistance means to cure the disease, and remission of the disease process, microorganisms, parasites, and the tolerance of tumor cells to chemical drugs, resulting in drug efficacy gradually weakened. This thesis, the main technical means of computer-aided design methods to study the mechanism of P-glycoprotein multidrug resistance modifiers, and resistance androgen receptor inhibitors provide theoretical support for drug-drug design. First, the study, 70 P-glycoprotein (P-glycoprotein, Pgp) inhibition of the activity of compounds using the Hybrid method to establish quantitative structure-activity relationship (QSAR) models; followed by the application of molecular docking method to study two typical Pgp inhibitors of Pgp protein interactions. Preliminary study found that cell lines produce most of the multidrug resistance associated with overexpression of Pgp, but its mechanism is not completely understood. In order to find a more effective Pgp modifiers, application of QSAR model can effectively reduce the design fee of P-glycoprotein inhibitors, improve the efficiency of drug development, the project consolidated multiple linear regression and support vector machine model, to establish Hybrid hybrid model use strict inspection standards, its predictive ability is better than a single model for prediction set, test set, and the overall data set. Meanwhile, the application of molecular docking method to study the two typical Pgp inhibitor of Pgp protein interactions, results show that the degree of active cavity ligands Pgp protein hydrophobic and electrostatic parts of the match is the main factors to affect the binding and explain the different activity differences between the inhibitor. Secondly, for the study of the drug resistance of the androgen receptor inhibitor, select groups of wild type and mutant male hormone receptors are a compound having an inhibitory action, the method of using the flexible docking investigated butt around the receptor and the ligand conformation change, from the molecular level to explore the mechanism of action of the wild type and mutant androgen receptor resistance inhibitors. Prostate cancer is the second largest cancer treatment leading to the death of Western men take androgen deprivation therapy, between 18-24 months, however, will be upgraded to a castration-refractory prostate cancer. Mutations in human prostate cancer cell lines led to the androgen receptor in androgen and non-androgen and anti-androgen generate response effect, and that led to the emergence of drug resistance. Therefore, for the mutant androgen receptor inhibitors effectively reduce the resistance has important significance. In this study, by means of semi-flexible and flexible docking simulations 8 androgen receptor inhibitor with wild-type and mutant androgen receptor binding process, androgen receptor inhibitor resistance mechanisms. Found that inhibitors of molecular volume greater impact in the process of integration with the receptor protein; greater the volume, the greater the change of the RMSD values ??of the receptor protein. Analysis of wild-type and mutant proteins before and after docking binding site amino acids RMSD values, found that derivatives of bicyclic-1H-indole -1,3 (2H) and the wild-type and mutant male hormone receptor was inhibited by calculating the inhibitors induced receptor of the long-chain amino acid residue MET780 and ASN705 conformational changes. Show that these two amino acid residues are critical amino acids affect inhibitor activity of wild-type and mutant androgen receptors, reasonable ideas for the structural design of these drugs

Investigate the P-glycoprotein Modulators and Androgen Receptor Antagonists Base on the Computer Aided Drug Design Methods

Abstract

Related Dissertations