Computational Discovery of CDK8 Inhibitors From Natural Compounds in NPACT Database

Cyclin-dependent kinase 8 (CDK8) is a crucial transcriptional regulator and promising anticancer target. This study screened NPACT natural compounds to identify potential CDK8 inhibitors. Twenty-seven candidates showed strong binding (ΔG < -11 kcal/mol). Molecular dynamics confirmed stable complexes, with key interactions involving Asp173, Phe97, and Lys52. Steered MD revealed strong correlation with experimental affinities (R = -0.744). Compounds such as amentoflavone and artoindonesianin A showed higher pulling work than known inhibitors. Toxicity prediction indicated mostly low-to-moderate risk. These findings suggest that several natural compounds as promising CDK8 inhibitor leads, warranting further experimental validation.