Computer-aided Structural Design And Theoretical Study Of DNA Topoisomerase ? And CDK8 Inhibitors

In this paper,two kinds of antitumor DNA topoisomerase I and CDK8 inhibitors were systematically studied by computer aided method.Part one:60 evodioids were superimposed based on a pharmacophore model to obtain a reliable and highly predictive comparative molecular field analysis(COMFA,q~2=0.729,r~2=0.985)and comparative molecular similarity index analysis(COMSIA,q~2=0.746,r~2=0.989)models.By molecular docking and molecular dynamics,the hydrogen bond produced by the inhibitor with the residues GLU356 and ARG364 and the hydrophobic interaction with base TGP11,DA113 play an important role in protein stability of the inhibitors,the electrostatic field had the greatest influence on the residues ASN722 and THR718 in the DNA minor groove,to ensure that the compound produces better inhibitory activity,the molecular structure should be planarized and appropriate in this region.Through virtual screening and structure-activity relationship(SAR),we obtained ten(DS1-DS8,z1-z2)well predicted compounds.Part two:We studied the structure-activity relationship of CDK8 inhibitors.The COMFA(q~2=0.64,r~2=0.98)and COMSIA(q~2=0.609,r~2=0.952)models of 39 CDK8inhibitors based on the common skeleton are reliable and have the ability to predict.Through the analysis of modeling,it was found that the activity of the compound is most affected by the fields of electrostatic and hydrogen bond acceptor.Molecular docking showed that LYS52,ASP98,ALA100 and ARG356 are important residues in the receptor binding site.Results revealed that the hydrogen bond interaction with LYS52 residue remarkably affects the activity of the compound.Based on the results of the study,the compound DS1 was designed with introduction of fluorine to an naphthyridine ring,two screening methods were used to screen the ZINC database containing 10,000 small molecules to obtain 14 carbazole compounds,all of them can be used as candidate compounds for the future study.The above results established important foundation basis for the study of the anti-tumor effects and structural design of these two inhibitors.