Study On Statistical Screening Of Traditional Chinese Medicine Prescriptions For Anti-Prostate Cancer And Structure-activity Relationship Study Of AR Antagonists

Prostate cancer?PCa?,an epithelial malignancy that occurs in the prostate,reminds the second leading cause of cancer-related incidence in men worldwidely,close to the first lung cancer.In 2018,an estimated 1276106 cases of prostate cancer were newly diagnosed and about 358989 died from this disease.The incidence varies by geography,ethnicity,age,and diet,for example,the incidence in Europe and the United States is higher than in Asia,Older people over 65 are more likely to develop the disease.With the influence of many complicated reasons such as western dietary habits,lifestyles,and gradual entry into an aging society,the incidence of prostate cancer in China is increasing.Androgen receptor?AR?,a ligand-dependent transcription factor that belongs to the steroid hormone receptor family,was considered to be the key targets for prostate cancer.When the androgen is combined with the AR,the structure of the AR is changed to a dimer structure,which promotes nuclear transcription and increases the expression level of the androgen receptor,leading to prostate cancer.Therefore,the AR is also the core target for prostate cancer research.Although there are many drugs inclinic,such as flutamide,bicalutamide and enzalutamide,none of them is not resistant.In chapter 1,we describe PCa,including current disease status,treatments,and castration-resistant prostate cancer?CRPC?.Then the structure,function,and signaling pathways of AR,androgens receptor antagonists are introduced.Finally,the prescription of traditional Chinese medicine for prostate cancer is expounded.In chapter 2,to explore the 2D quantitative structure-activity relationship?2D-QSAR?between molecular structures and corresponding binding abilities to aid new molecules with better androgen receptor affinity activity design,multiple linear regressions?MLR?are employed to analyze a series of hydantoin analogues,The obtained model has reliable and powerful predictive power and can be used to predict the binding capacity of unknown chemicals.Then using comparative molecular field analysis?CoMFA?and comparative molecular similarity indices analysis?CoMSIA?methods to construct a three-dimensional quantitative structure-activity relationship?3D-QSAR?and to analyze the relationship between a series of androgen receptor antagonist 3-phenylpyrazole derivatives and their antagonistic activity.Two different methods were used to obtain the 3D-QSAR model,one is based on atomic alignment and the other is based on molecular docking,which provides key structural features highly related to the biological activity of androgens,and provides valuable guidance for the design of new androgen receptor antagonist in the future.In chapter 3,a virtual screening method is used to conduct preliminary screening of the components of traditional Chinese medicine for prostate cancer to obtain candidates.The biological activity of candidates is verified by biological experiments,and MoL₁1 with the best activity is obtained.Molecular dynamics simulations is utilized to study the mechanism of MoL₁1 with wild-type AR and mutant AR?F876L?,and predict whether MoL₁1 would have an effect on drug resistance caused by the positive drug Enzalutamide with a view to discovering novel androgen receptor antagonists.In this thesis,a method combining computer-assisted drug design and biological experiments is provided to predict the binding activity of androgen receptors to unknown compounds,the structural characteristics of androgen receptor antagonists that are highly related to biological activity are revealed.MoL₁1,a small molecule with better activity and no resistance to F876 L androgen receptor is screened out,which provides theoretical basis and constructive reference for the design and modification of novel androgen receptor antagonists in the future.