| The exact pathogenesis and targets of Chronic Prostatitis/Chronic Pelvic Pain Syndromes(CP/CPPS)have not been fully elucidated.There are no effective treatments and drugs,which makes it difficult to cure the recurring symptoms and is listed as one of the most serious chronic diseases affecting people' s quality of life.To solve this core problem,the peptide T2 is used as a probe molecule by in silico analysis to investigate the interaction mechanism between T2 and T-cell immunoregulatory proteins closely related to CP/CPPS,and screen the immunoregulatory proteins strongly associated with peptide T2.The interaction sites and key structures between peptide T2 and the immunoregulatory protein were studied,and novel peptides with better affinity and selectivity with the protein were designed.In vitro activity experiments were carried out to verify the activity of novel peptide,from which the relationship between the immunoregulatory proteins screened above and CP/ CPPS was deduced,and possible targets of CP/ CPPS were found.Accordingly,small molecule inhibitors of PD-1/PD-L1 immune checkpoint pathway were designed.It is of great theoretical and clinical significance for revealing the pathogenesis,drug design and development,clinical diagnosis and treatment of CP/CPPS,and is of great social significance.This thesis consists of four sections:Chapter 1: This chapter outlines the definition and characteristics of CP/CPPS,and summarizes current advances in the study and development of PD-1/PD-L1 inhibitors.Consequently,this chapter briefly introduces the development of computer-aided drug design,commonly used calculation methods and basic principles.In addition,calculation methods used in this thesis are also underlined.Finally,the basis and main research contents of this thesis are described.Chapter 2: Based on the docking results of PD-1 protein and peptide T2,this chapter designed 13 novel PD-1/PD-L1 blockers based on the binding region and interaction mechanism of peptide T2 and PD-1 protein.The 13 novel peptides were docked with the PD-1 protein.Through the analysis of the scoring function,the distribution of the docking posture,the force on the docking interface,and the binding energy,five PD-1/PD-L1 peptide blockers with stronger binding and higher activity to the target protein PD-1 were finally selected.which were completely consistent with the results of biological activity testing experiments in vitro.This not only plays an important guiding role for the rational design and modification of peptide drugs,but also lays a basis foundation for subsequent animal experiments in vivo.Chapter 3: On the basis of the above research,this chapter selects human PD-1protein as the receptor protein,and the key amino acids GLU136,LYS78,TYR68 and the enclosed cavity were selected as the active center.Two databases of Specs and Pkucncl databases were selected,and ADMET prediction study was carried out for subsequent bioactivity tests.It also provides important ideas and theoretical support for the design and development of novel PD-1/PD-L1 inhibitor molecules.Chapter 4: This chapter selects 28 biphenyl compounds with good inhibitory effect against PD-1/PD-L1,which can inhibit the PD-1/PD-L1 pathway,and the interaction surface of PD-1 could be occupied by another PD-L1 protein by inducing PD-L1 dimerization.Therefore,pharmacophore simulation,virtual screening based on pharmacophore model,molecular docking,and ADMET prediction research were performed.Molecular docking was used to analyze the possible binding mode and active conformation between inhibitors and PD-L1,on which the pharmacophore simulation method was used to establish a reliable statistically significant model AAHRRR.1.Then,the optimal model was employed in the Specs and Pkucncl databases to screen the molecules matching to the pharmacophore.Finally,according to ADMET prediction and molecular docking studies,ten suitable molecules were selected for subsequent biological activity experiments. |
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