Studies On The Discovery And Mechanism Of Lead Compounds With Anticancer Activity Based On In Silico Anticancer Models

Generally,drug research and development(R&D)includes lead compounds discovery,lead compounds optimization,and clinical trial research.Therefore,discovering lead compounds plays a key role in drug R&D because it directly relates to whether drug R&D projects can achieve success or not.Lead compounds can be discovered using target-and phenotypic-based drug screening.Recently,Phenotypic-based drug screening and its new definition referred to as modern phenotypic drug screening have been widely concerned and used in drug R&D,because it is closely related to diseases so as to led the discovery of first-in-class drugs.Pervious study demonstrated that the first-in-class drugs were mainly discovered based on phenotypic drug screening,which showed an increasing trend.While the discovery of the follower class drugs mainly depended on the target-based drug screening methods.Modern phenotypic-based drug screening consists of cell-,tissue-,organ-,and animal-based drug screening models.The research methods used in phenotypic drug screening are not only limited to pure experimental approaches,but also include computer-aided drug design(CADD)and other methods.Lead compounds with cellular activity can bridge its activities for a given target and a related animal-based disease model.In the present study,in silico anticancer activity prediction models were established based on the NCI-60 cell-based drug screening data using machine learning methods.The established models were successfully evaluated by five-fold cross validation,external test set,and Y-Scrambling test.Then,a virtual screening campaign was designed to screen ChemDiv database(18219 compounds)based on the best proposed models.Fourteen compounds exhibited anticancer activity against five tumor cells and G03 is the most potent compound with IC50 values of 2.82 μM,2.90 μM,2.98 μM,3.20 μM and 4.61 μM,against MDA-MB-231,Hela,HCT-116,HepG2 and MCF-7,repectively.Identifying the molecular target for lead compounds from phenotypic screening is significant.In this study,tubulin is identified as a major target for G03 through the molecular similarity-based target fishing and SPR assay.Microtubules have important effects on cell cycle,cell migration,and other physiological processes.Therefore,G03 were also tested against microtubules-related function in tumor cell.The first chapter introduces the current strategies and progress of drug discovery and the research progress of NCI-60 drug screening platform.The second chapter introduces the construction and evaluation of in silico anticancer activity prediction models based NCI-60 cell-based drug screening data.In the third chapter,the discovery of anticancer lead compounds based on NCI-60 anticancer activity prediction models will be introduced.The fourth chapter studies on the mechanism of the most potent lead compound G03.The fifth chapter gives the prospect and summary of the whole project.