Design And Synthesis Of Computer Aided Drug Design NA And Limk1 Inhibitors

Influenza is an epidemic disease that is widespread every year.At present,neuraminidase(NA)is considered as a key target of influenza virus and plays a key role in the spread of influenza virus in cells.In this paper,a data set of 21 caffeic acid derivatives of known structure was constructed using the 3D-QSAR model.The quantitative structure-activity relationships include two methods: molecular position analysis(CoMFA)and comparative molecular similarity analysis(CoMSIA).In addition,the key interaction information of the binding of the compound and the protein was obtained through molecular docking.The results showed that the carbonyl oxygen and the hydroxyl hydrogen atom of the compound were the key positions of the hydrogen bonding,and the benzene ring and the terminal alkyl group were the key positions of the hydrophobic interaction.Finally,according to the quantitative three-dimensional structure-activity relationship calculations and molecular docking calculations,10 new compounds were designed and the biological tests of the new compounds were completed.The results of the activity showed that the new compounds have a good inhibitory effect on neuraminidase.In addition,as an important serine/threonine protein kinase,LIMK1 plays an important role in the assembly of the actin-containing cytoskeleton in the cytoplasm.In the study of LIMK1 inhibitors,we found that the pyrrolopyrimidine structure and fluorine atom at the benzene ring can increase the inhibitory effect of the compound significantly.In this paper,the results of molecular docking indicated that the pyrrolo-pyrimidine structure of the compound and the key residues Ile416 and Glu414 in the hinge region of limk1 had an important hydrogen bonding forces,besides the position of the fluorine atom was formed H-bond forces with the key residue Gly346 of limk1.The stability of the docking results was verified by molecular dynamics simulations.In addition,the calculation of binding free energy also proved that the key residues of the force formed at the fluorine atom and pyrrolopyrimidine positions account for a large proportion of the free energy of binding of the complex.The proportion of energy in the compound plays a positive role in the active site of the compound binding protein,so that the inhibitory activity of the compound is improved.