Quantitative Structure-activity Relationship Study Of ERR? Inverse Agonists And Design And Synthesis Of Novel Compounds

Cancers are a large family of diseases that involve abnormal cell growth with the potential to invade or spread to other parts of the body.In the latest report of 2018,about 70% of the 9.6 million cancer deaths in the global are in Asia,and cancer morbidity and mortality of China are the highest in the world.Currently,the therapy of cancer is still using traditional treatments such as radiotherapy,surgery and chemotherapy.However,medicine used in chemotherapy is mostly cytotoxic anti-tumor drugs possessed different side effects.Therefore,molecular targeted therapy has become a hot spot in the field of cancer treatment in recent years.Molecular targeted therapy blocks tumorigenesis by interfering with specific molecules required for cancer cell growth and growth,rather than simply interfering with all rapidly dividing cells as traditional chemotherapy.Because most drugs for targeted therapy are biopharmaceuticals,they can also be called biological therapies.Estrogen-related gamma receptors(ERR?)and Bruton's tyrosine kinase(BTK)and have been identified as very important cancer-related biological targets.This paper is divided into two parts: The first part is the study of estrogen-related ? receptor inverse agonists.Firstly,the reported ERR? inverse agonist with known structure and activity are collected into a database;then,the PDB protein crystals of the reported ERR? receptor were reviewed and downloaded,and the inverse agonist acting on the ERR? receptor was docked to the active pocket by the docking technique in the SYBYL software,and the important amino acid residues of the small molecule interacting with the protein were found such as Glu275,Arg316 and Tyr326.After that,we studied the quantitative structure-activity relationship of ERR? inhibitors by computer-assisted drug design.According to the obtained rule,we designed a novel skeleton of ERR? small molecule with bisbenzenesulfonamide structure.Finally,we selected 6 compounds with higher scoring to carry out the synthesis experiment,and then the synthesized products were subsequently screened for in vitro activity at the molecular level,and the molecular structure was further optimized and modified by the feedback activity data,so that it is expected to finally synthesize high activity and high safe drug precursor molecule.This paper provides a clue and empirical basis for the synthesis of novel ERR? receptor inverse agonists.The second part is the research work on BTK inhibitors.This section has carried out two series of studies on the structure of the mother nucleus,namely the carbazole core and cinnoline core.The research content is firstly to collect all the molecules with the corresponding parental structure into a database,and to view and download the relevant PDB protein crystal complex.Then study the molecular docking and quantitative structure-activity relationship(3D-QSAR),summarize and analyze the obtained rules,and get the information of the next step of small molecule structure optimization.Moreover,we followed the two series of comparison analysis to design 13 new BTK inhibitors with higher scoring and reasonable conformation.