| As a key member of the nuclear receptor family,RXRa exerts genomic or non-genomic functions in the form of homodimers or heterodimers,and participates in physiological processes such as cell proliferation,survival,apoptosis,and inflammation.The abnormality of RXRa function and level is closely related to the occurrence and development of metabolic diseases,neurodegenerative diseases and cancers.Thus,RXRa has been an important target for drug development.At present,the ligand binding sites of RXRa include classic ligand binding pocket(LBP),tetramer ligand binding site and coactivator binding site(CBS).Among them,drugs targeting LBP of RXRα have toxic and side effects such as hyperlipidemia and hypothyroidism,so targeting non-LBP sites has become a new hot spot for nuclear receptor drug development.Our research group reported earlier that the sulindac derivative K80003 targeting the ligand binding site of RXRα tetramer and the 8533 series of compounds targeting RXRα-CBS have good pharmacological effects.Based on this,this thesis continues to develop and optimize new ligands that specifically target RXRα-CBS through "peptidomimetic design" and virtual screening methods,providing new ideas for the development of anti-tumor drugs based on RXRα.First,based on the structural characteristics of the interaction between RXRa and coactivator,we used "peptidomimetic design" to construct two scaffolds for a total of 9 compounds.After molecular docking assessment,we performed chemical synthesis.Through biological experiments such as reporter gene,we found that compound XS987 can inhibit the transcriptional activity of RXRa and effectively inhibit the mitosis of cancer cells.Cell flow cytometry experiments show that XS987 has a good cell cycle arrest effect,and the KD value of its binding to RXRα is 4.538 μM through fluorescence titration experiments.We also designed and derivatized the framework,obtaining 11 derivatives of XS987.Their structure-activity relationship was summarized,and finally a lead compound XS1011 with enhanced activity was optimized.In order to continually searching for new backbone hits that may target the CBS of RXRα,virtual screening method was used to conduct molecular docking of the 110,000 compoundsfrom commercial compound database Chembrige and compound 8533 was set as a reference compound for comparison.Maestro 11.9 software was used and SP,XP,RMSD andMMGBSA were calculated step by step,combined with the cluster analysis function of Canvas 3.9.According to the binding pose and binding energy of the top compounds,we finally screened 26 potential coactivator binding site inhibitors(CBIs)targeting RXRα.ADMET prediction indicating that they have good druggability.Currently,the series of compounds are undergoing biological activity evaluation.In order to reduce the impact of the pandemic of S ARS-Cov-2 on our scientific research,this thesis once again uses virtual screening technologyand the Chembrige database,to theoretically predict new inhibitors targeting the Mpro of SARS-CoV-2,and this would promote the drug discovery for the treatment of COVID-19.A large number of studies have shown that the Mpro of SARS-CoV-2 is the key hydrolase in the process of virus replication,and there is no similar protease in human body.Therefore,the development of SARS-CoV-2 specific Mpro inhibitors is an effective method for the treatment of SARS-CoV-2 infection.Finally,we used the classical ligands X77 and 3WL of Mpro of SARS-CoV-2 as reference compounds,and top 15 compounds were screened with good binding energy through HTVS,SP and XP mode molecular docking.Through further molecular dynamics simulation,the RMSD,RMSF and MMGBSA calculation results indicated that compounds 4,6 and 11 have potential inhibition toward Mpro of SARS-CoV-2.The results of ADMET prediction showed that these compounds had good drug likeness properties.At present,the biological activities of these compounds are being tested. |
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