Structure-activity Relationships Analysis,Virtual Screening And Bioactivity Evaluation Of Androgen Receptor Antagonists

Prostate cancer?PCa?is a common male malignant tumor and the second leading cause of cancer-related death over the world.Researchers pointed out that the incidence of prostate cancer is characteristic of geographical and ethnic differences,especially in the developed countries.Recently,because of the improvement in prostate-specific antigen screening,biopsy techniques and impact on increasingly westernized lifestyle,the numbers of new prostate cancer cases increased rapidly in China.When binding with androgen,androgen receptor?AR?can be activated and regulates the gene expression and growth of prostate cancer cells.Therefore,AR is the major target for the therapy of prostate cancer.Nowadays,available drugs targeting AR mainly include flutamide,bicalutamide,enzalutamide,and abiraterone.All the antiandrogens above are effectively at the beginning,but drug resistance problem appears thereafter.Though the specific mechanism about resistance for antiandrogens is unclear,AR mutation,AR splicing variant,aberrant activation of PI3 K pathway,Wnt pathway and EGFR pathway transformed antiandrogens from AR antagonists to agonists.In the first part of this thesis,we presented prostate cancer briefly,including the state in China and aboard,diagnose and treatments.Additionally,we introduced the information of AR,mechanism of drug resistance for prostate cancer,and small molecular inhibitors of different targets.In the second part,two-dimensional multiple linear regression?2D-MLR?,3D comparative molecular field analysis?CoMFA?and comparative molecular similarity indices analysis?CoMSIA?methods were employed to construct quantitative structure-activity relationship?QSAR?models to further explore the structure-activity relationships of a series of carbobicyclo and oxabicyclo succinimide analogues,which would reveal the key structural features related with the bioactivity.The QSAR models can be used to guide the modification of lead compounds,and meanwhile these models can also be employed to predict the corresponding bioactivities of the modified novel compounds.In the third part,computer-aided virtual screening and activity evaluation were employed to discover the novel AR antagonists.Firstly,the structure based virtual screening including LibDock and Glide docking were used to identify the molecules of high affinity with AR and Lipinski's rule of five and veber rule were the criteria that could evaluate the drug likeness for molecules.Secondly,the ADME parameters were calculated on these selected molecules to predict the pharmacokinetic properties.We applied cluster analysis based on structural similarity and picked out the representative molecules of each cluster.Finally,the molecule 10?MOL₁0?was found to be a potential AR antagonist according to the results of cell proliferation and AR reporter gene assay.In the fourth part,we adopted molecular dynamics?MD?simulation to explore the interaction mechanism between MOL₁0 and wild type?WT?AR and F876 L point mutated AR.Based on resistance study for enzalutamide in-house,we combined the result of stable system,hydrogen analysis,interaction mode,binding free energy,decomposed binding free energy to study the interaction mode with WT AR,and predict whether the F876 L AR could give rise to resistance or not according to the interaction mode between MOL₁0 and F876 L AR.In this paper,the models of quantitative structure-activity relationship for carbobicyclo and oxabicyclo succinimide analogues were constructed,and the novel androgen receptor antagonists and interaction mechanism were studied through virtual screening,bioactivity evaluation and molecular dynamics simulations,which laid a foundation for discovery novel androgen receptor antagonists.