Computational studies to identify the common type-I and type-II inhibitors against the CDK8 enzyme

In this study, multicomplex-based pharmacophore modeling was conducted on the structural proteome of the two states of CDK8 protein, that is, DMG-in and out. Three pharmacophores having six, five, and four features were selected as the representative models to conduct the virtual screening process using the prepared drug-like natural product database. The screened candidates were subjected to molecular docking studies on DMG-in (5XS2) and out (4F6U) conformation of the CDK8 protein. Subsequently, the common four docked candidates of 5XS2 and 4F6U were selected to perform the molecular dynamics simulation studies. Apart from one of the complexes of DMG-in (5XS2-UNPD163102), all other complexes displayed stable dynamic behavior. The interaction and stability studies of the docked complexes were compared with the references selected from the two conformations (DMG-in and out) of the protein. The current work leads to the identification of three common DMG-in and out hits with diverse scaffolds which can be employed as the initial leads for the design of the novel CDK8 inhibitors.