| Apoptosis is a process of programmed cell death that is autonomously controlled.Dysregulation of this process can lead to malignant cell proliferation and carcinogenesis.The Bcl-2 family of proteins are the most important regulators of the intrinsic pathway of apoptosis,with myeloid cell leukemia 1 protein(Mcl-1)being a crucial member.Mcl-1 is widely expressed in normal human tissues such as epithelial cells,cardiomyocytes,and lymphocytes,but its abnormal expression can lead to the development of many malignancies.Mcl-1 dependent acute leukemia,lymphoma,non-small cell lung cancer,and breast cancer cells can be effectively eliminated by inhibiting Mcl-1.Furthermore,Mcl-1 is associated not only with the development of cancer but also with resistance to chemotherapeutic drugs during later stages of cancer treatment.For this reason,Mcl-1is a valuable target for anticancer therapy.Research on Mcl-1 inhibitors has made great progress in recent years,with six drugs entering clinical trials along with other investigational drugs.However,all of them have shown some degree of cardiotoxicity in clinical trials.Currently,there are no successfully marketed selective Mcl-1inhibitors that can be widely used in clinics.Therefore,it is crucial to investigate and discover novel lead compounds of Mcl-1 small molecule inhibitors for cancer treatment and to tackle drug resistance problems associated with certain drugs.The first chapter of the thesis comprises five sections.The initial four parts concentrate on Mcl-1,describing its structure,mechanism of action,the development of small molecule inhibitors entering clinical trials,and Mcl-1-dependent cancers,as well as the challenges related to Mcl-1 small molecule inhibitor research.In the final section,we present a concise introduction to computer-aided drug design,followed by elaboration on molecular docking and virtual screening components that will be employed in this thesis.The second chapter of the thesis focuses on ligand small molecule screening of Mcl-1 protein targets using computer-aided drug design and obtaining candidate compounds.The screening process involved rapid Lib Dock docking of the Inter Bio Screen compound library to obtain initial screening compounds.These results were then subjected to Glide precision and clustering to identify preliminary candidate compounds that bound well to the Mcl-1 protein after interaction analysis.The third chapter of the thesis involves validation of the biological activity of candidate compounds.Firstly,we screened various cell models and found that MV4-11 cells had higher Mcl-1 expression.For activity validation,the growth viability of these cells was measured.Our results showed that the small molecule STOCK2S-00581 exhibited a higher cytostatic rate than the positive drug by MTT assay.It was therefore selected for further validation of Mcl-1,Bcl-2,and Caspase 3 protein expression levels.We found that this compound selectively increased Mcl-1 protein levels,exhibiting better cellular activity.Chapter 4 of the thesis analyzes the most potent Mcl-1 inhibitors in terms of their hydrogen bonding,π-π interactions and hydrophobic interactions with target proteins.Subsequently,system stability and binding free energy were analyzed through molecular dynamics simulations for both the small molecule STOCK2S-00581 and the positive drug.The drug-protein interactions were explained in detail from a molecular perspective.In this thesis,we utilized Mcl-1 as the target for molecular docking and drug-like screening of the IBS small molecule database.This approach allowed us to identify 11 compounds with potential Mcl-1 binding abilities and differing molecular backbones using clustering analysis.Upon experimental validation,including cell viability assays and key protein expression level change assays,a novel Mcl-1 inhibitor lead compound STOCK2S-00581 was identified.This discovery provides both a theoretical and material basis for the identification of potential high-level Mcl-1 inhibitors. |
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