Investigate The P-glycoprotein Modulators And Androgen Receptor Antagonists Base On The Computer Aided Drug Design Methods

Drug resistance, the reduction in effectiveness of a drug in curing a disease or improving patient symptoms, can develop against antibiotics, antivirals, or chemotherapeutic agents for cancers. Thus, Computer-aided Drug Design (CADD) methods have been devoted to do some study about the mechanism of action of P-glycoprotein (Pgp) modulators and Androgen receptor antagonists.First of all,70 multiple drug resistance (MDR) modulators were build a hybrid QSAR model for predicting modulating activity based on single multiple linear regression (MLR) models and support vector machine (SVM) models. Moreover, molecular docking method was used to study the interaction between two typical Pgp modulators and Pgp.Multidrug resistance is the primary mechanism that leads to the acquisition of the multiresistant phenotype through the overexpression of drug efflux transporters such as the. Though the mechanism of Pgp is not understood in detail, tremendous efforts are being made to find out modulator molecules to inhibit Pgp.The hybrid method was proved to be a very promising tool in the prediction of MDR-modulating activity. Additionally, the application of strict validation criteria permits the high quality of the hybrid model. Thus, these in silico methods can be applied to predict this property in the early stage of drug development and some of them will be important tools to select new drug candidates. Moreover, molecular docking method was used to study the interaction between two typical Pgp modulators and Pgp.Results show that the hydrophobic and electrostatic interaction played an important role in the stabilization of the binding mode. The results of molecular docking can be good consistent wih the diversity of antagonist activity.Secondly, flexible molecular docking was used to investigating the transformation of mode of two group compounds binding to the wide type (WT) androgen receptor (AR) and mutant type (MT) AR. It is also useful for us to understand the mechanism of action of these AR antagonists.Prostate cancer (PC) is the second leading cause of cancer-related deaths among men in Western countries. Though patients with PCa initially respond to androgen-deprivation therapy (ADT), they inevitably relapse to castration-resistant prostate cancer (CRPC) within 18-24 months. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. Thus, development of compounds which yielded potent antagonist activity against the WT AR as well as the MT AR is very significant. Eight AR antagonist compouds were docked to the WT and MT AR throught the half flexible and full flexible docking methods. These docking experiments revealed that the volume of compounds can largely influence the binding. Because of the induced-fit effect, the lager of the compouds, the bigger of the Root mean square deviation (RMSD) Meanwhile, the two residues MET780 and ASN705 have been calculated for great RMSD. It can be deduced that this two residues are key residues for the antagonist activity. It can also provide research ideas for rational drug design.