Discovery Of Inhibitors Targeting Talin1 And RBM4 Proteins Based On Novel Virtual Screening Tools

Virtual Screening is the core of computer-aided drug design.It is based on the three-dimensional structure or quantitative structure-activity relationship model of target biological macromolecules,the theory of molecular biology and computer science and other related fields is used as a technology support.Known types of small-molecule databases can be used to select compounds that meet the desired target,thereby realizing targeted drug screening and design for specific diseases.There are many tools currently used in scientific research to predict the binding of proteins and small molecules,such as AutoDock,but these tools also have many problems.Therefore,there is an urgent need to develop a molecular docking tool with higher sampling efficiency and accuracy.This laboratory applies global information sharing group intelligence technology(FIPS)to the problem of conformation sampling of molecular docking,and has independently developed a new generation of molecular docking tools FIPSDock.Through the optimization of the search method,FIPSDock has the advantages of faster sampling and higher precision than currently used commercially available docking software.Therefore,this paper is based on FIPSDock technology,targeting Talin1 protein and RBM4 protein related to tumor metastasis,invasion,and other aspects,as a receptor structure for the virtual screening and design of drugs.Since Talin1 protein is involved in the activation of integrins,and the activation of integrins is inseparable from the development of tumors,the Talin1 protein and integrin activation-related sites are used as targets for drug screening in this paper.The inhibitors were screened against this target in order to achieve targeted inhibition of tumor development.The other target protein RBM4,due to the binding of CCHC zinc finger domains in its domain with pre-mRNA,can stabilize the binding of RBM4 to pre-mRNA,thereby promoting the development of tumors.Therefore,CCHC-type zinc finger domain was used as the target site for drug screening in this dissertation.It intends to destroy the structure of CCHC-type zinc finger domain and block the binding of RBM4 to pre-mRNA and ultimately inhibit tumor development.In this dissertation,the spatial three-dimensional structure of the two proteins was obtained by searching the receptor protein database and homology modeling.Due to the innovative nature of the target Talin1 protein pocket,the lead compounds of this target were not found.Therefore,two more typical natural product databases were selected as the source of ligand molecules to perform the virtual screening of targeted Talin1 protein.The RBM4 protein is highly homologous to the HIV-1 nucleocapsid protein NCp7 due to its CCHC-type zinc finger domain.Therefore,there may be similar binding sites and the ability to recognize chemically similar ligands,and there are a large number of reports on NCp7 protein inhibitors,so the NCp7 protein inhibitors have been reported as a ligand molecule for virtual screening.Through the scoring function of the two protein virtual screening results and the specific interaction mechanism,the ideal inhibitor small molecule or drug design based on the lead compound was selected.Using molecular dynamics simulation methods,the binding of ligands to protein receptors was further analyzed by calculating RMSD,RMSF and other kinetic parameters,and analyzing the free energy of receptor-ligand interactions.In the end,preliminary ideal inhibitor molecules were obtained.