Design And Biological Activity Evaluation Of PD-L1 Small Molecule Inhibitors Based On ARAE Model

BackgroundTumor immunotherapy has achieved extraordinary results in clinical,making cancer immunotherapy has become an emerging tumor treatment method after traditional chemotherapy,radiotherapy and surgery.Currently the most widely used immunotherapy target drugs are PD-1/PD-L1 monoclonal antibodies.Although the clinical effect of monoclonal antibody drugs is remarkable,there are still some undeniable problems,such as the complex preparation process of monoclonal antibody drugs,high price,limited to intravenous and subcutaneous administration.Compared with monoclonal antibodies,small molecule drugs have significant advantages such as low price,oral administration,easy transportation and storage,good membrane permeability and non-immunogenicity.Therefore,the search for PD-1/PD-L1 small molecule inhibitors has become a hot spot for new drug development.ObjectiveIn this study,we applied an adversarially regularized autoencoder（ARAE,adversarially regularized autoencoder）method to design novel small molecule inhibitors of PD-L1,and use PD-1 Effector Cells and PD-L1 a APC/CHO-K1 Cells cell lines,demonstrated Biological activity of PD-L1 small molecule inhibitors.Methods1.This experiment adopts the artificial intelligence drug design method（ARAE）.A new PD-L1 small molecule immune checkpoint inhibitor was designed,and a total of 6 PD-L1 small molecule inhibitors were screened and designed.2.The EC50 values of 6 PD-L1 small molecules and their cytotoxicity to T cells were determined by biological activity experiments,and two PD-L1 small molecule inhibitors Compound 5 and Compound 6 were chosen.3.The genetically engineered cell lines PD-1 Effector Cells（ECs）and PD-L1 a APC/CHO-K1 Cells（a APC）were used to measure Compound 5,Compound 6,PD-1antibodies（nivolumab and pembrolizumab）and PD-L1 antibodies（atezolizumab and durvalumab）,and their EC50 values and maximum luminosity（RLU）were calculated.Results1.The cytotoxicity of Compound 5 and Compound 6 on T cells is lower than Compound1、Compound 2、Compound 3、Compound 4,and the LD50 values are relatively high,which is suitable for subsequent experiments.2.Compound 5 and Compound 6 can block the binding of PD-1 and PD-L1,and activate the the activity of T cells.3.Compared with PD-1/PD-L1 monoclonal antibodies（nivolumab,pembrolizumab and atezolizumab,durvalumab）,the EC50 values of Compound 5 and Compound 6 are higher than PD-1/PD-L1 monoclonal antibodies,indicating it is efficacy is less than monoclonal antibodies,and the activation level of activated T cells is not as strong as PD-1/PD-L1 m Ab.ConclusionIn this study,through the antagonistic regularization autoencoder（ARAE）,a small molecule inhibitor of PD-L1 was designed and screened with the ability to block the binding of PD-1/PD-L1...