The Interaction Between CYP19 And CPR And The Virtual Screening Of Small Molecular Inhibitors

Breast cancer is a serious disease for women,with the progress of medical technology and the further research of breast cancer treatment,the methods of treatment are handled by people gradually.Aromatase is the main target for the treatment of hormone-dependent breast cancer.It is the rate-limiting enzyme in the last step of estrogen biosynthesis,the inhibition of aromatase can decrease the estrogen level so as to treat the hormone-dependent breast cancer.Thus,aromatase inhibitors become a hot spot of the research,meanwhile,the study of aromatase and its function begins to draw more attention.Through this work a template-based protein model of aromatase(CYP19)and mutant NADPH-cytochrome P450 reductase(mCPR)complex was constructed.With NAMD program,the molecular dynamics simulation was run and a stable complex of CYP19 and mCPR was got.The result showed that mCPR in its open form could combine with aromatase from proximal face steadily.The data showed that on the binding surface,there are H-bonds and 4 salt bridges,which contributed to the interaction between the two proteins.Through HARLEM software,the optimal pathway of the electron transferring from mCPR to aromatase was clarified.The electron transfer rates are 1.04×106 s-1 and 4.86×105 s-1 from FMNH2 to heme in solvent mediated and non-solvent mediated models respectively.The data showed that in solvent mediated model the electron transfers faster,which means that the solvent helps with electron transfer.Besides,a virtual screening was conducted based on the ZINC database with a pharmacophere model for noble small molecular inhibitors.556 data base files were screened,that was up to 12 million molecules.As a result,941 inhibitor-to-be molecules were got through the screening,cluster analysis showed that there are 3 characteristic types of molecules and molecule structure analyses were done in the end.In this research,we introduced a template-based protein alignment method to provide a new strategy for studying protein-protein interactions,which may offer plenty of help in the research of the electron transfer between the aromatase and CPR.Also a virtual screening was conducted,a lot of new molecules were got to lay a solid foundation for the development of better performance inhibitors.