Virtual Screening And Activity Evaluation Of Novel Androgen Receptor Antagonist

Prostate cancer is a serious disease in men,which is the second leading cause of male cancer-related death after Lung cancer in Europe and America.Although the incidence rate of prostate cancer in China is far low than Europe and America,with the accelerating aging process and the improvement of diagnosis,the incidence rate of prostate cancer has risen in recent years.AR antagonist is the mainly medium to treat prostate cancer.However,many commercially available drugs exist problems to be resolved.Firstly,patients will appear a variety of side effects after taking these drugs,such as gastrointestinal discomfort,nausea,vomiting,anxiety and loss of libido,etc.Secondly,after patients take single antiandrogen,the occurrence of a genetic mutation often results in the switch of an antagonist to an agonist.Therefore,there is a need to develop novel antiandrogenic skeleton in clinic.The first section of the present thesis firstly described androgen receptor,mainly including physiological function and clinical application of AR,gene and protein structure and function and biochemistry of endogenous agonists,then introduced nonsteroidal androgen receptor ligands,mainly including nonsteroidal androgen receptor ligands,nonsteroidal androgens and its advance in the treatment of prostate cancer.Finally,crystallography was used to illustrate the molecular binding mechanism of different pharmacophores.In the third section,receptor-based virtual screening method was used to screen molecule compound library.Finally some small molecule binds to AR with high affinity were screened and the structures were analyzed to obtain a series of novel compounds skeleton.In the third and fourth section,combining receptor-based virtual screening and ligand-based virtual screening methods was used to screen pyridinoimidazole derivatives.MTT assay demonstrated pyridinoimidazole derivatives can be used as androgen receptor antagonist,wherein compound ? can suppress the growth of prostate cancer cells,and the results are better than the first generation androgen receptor antagonist bicalutamide.The whole thesis by means of combining computer-aided drug design techniques and technology combined biological experiments,discovered a series of novel androgen receptor antagonist,the entire process for the future discovery and design of new anti-prostate cancer drugs provide ideas.