Virtual Screening Of New TGF-β Receptor Inhibitors And Research On Their Mechanisms

Tumor is one of the most common diseases that lead to human death today.There were 19.29 million new cancer cases worldwide in 2020,including 10.06 million males and 9.23 million females,and 9.96 million cancer deaths worldwide in 2020,including 5.53 million males and 4.43 million females.There are as many as 2.26 million new cases of breast cancer worldwide,more than 2.2 million cases of lung cancer.Breast cancer has replaced lung cancer as the largest cancer in the world.There were 4.57 million new cancer cases in China in 2020,including 2.48 million males and 2.09 million females.There were 3 million cancer deaths in China in 2020,ranking first in the world in terms of cancer deaths.The top 10 cancers in the world are breast cancer(2.26 million),lung cancer(2.2 million),colorectal cancer(1.93 million),prostate cancer(1.41 million),gastric cancer(1.09 million),liver cancer(910000),cervical cancer(600000),esophageal cancer(600000),thyroid cancer(590,000)and bladder cancer(570,000).These ten cancers account for 63% of the total number of new cancers.Transforming growth factor β(TGF-β)plays an important role in the occurrence and development of tumors and is highly expressed in many tumor tissues.At present,the drug design targeting TGF-β is mainly focused on the inhibition of TGF-β receptor.Many different kinds of small molecular inhibitors have been reported,and some of them have entered clinical trials.Traditional Chinese medicine is a treasure of Chinese traditional culture,and many ancient prescriptions still play an important role today.With the progress of technology,more and more monomers of traditional Chinese medicine have been analyzed,which makes it clear why traditional Chinese medicine plays a pharmacological role.At the same time,it also provides more effective means for clinical treatment.In this paper,some small molecular compounds and monomers of traditional Chinese medicine(natural products)with potential ability to inhibit TGF-β receptor were screened by computer-aided drug design.It is hoped that these compounds can be used as lead compounds and contribute to the discovery of new TGF-β receptor inhibitors.In the first chapter of this paper,a pharmacophore model is constructed by computeraided drug design.Furthermore,a new type of small molecular compound D481-2395 with the ability to inhibit TGF-β receptor was screened.The inhibitory effect of double fluorescein reporter gene on TGF-β was proved by double fluorescein reporter gene experiment.At the same time,it was proved that this compound can effectively inhibit the expression of TGF-β receptor and the expression of p-SMAD2 and SMAD4 in vitro.In cell experiments,D481-2395 can effectively inhibit tumor proliferation and metastasis.Therefore,D481-2395 can be used as a potential lead compound with the ability to inhibit TGF-β receptor.In the second chapter,the molecular docking method is used to dock the compound library of traditional Chinese medicine monomers and natural products with the protein structure of TGF-β receptor.Try to find traditional Chinese medicine monomers or natural products that can inhibit the expression of TGF-β receptor.We found that kaempferol 3-gentian disaccharides can inhibit the expression of TGF-β receptor in many kinds of tumor cells and affect the process of epithelial-stromal transformation by inhibiting SMAD pathway.