In Silico Discovery of Novel CDK1 Inhibitors from Linum Species for Targeted Cancer Therapy

Targeting cell cycle regulators such as cyclin-dependent kinase 1 (CDK1) represents a promising strategy for anticancer drug discovery. This study employed an integrated computational approach to identify natural CDK1 inhibitors from the ethyl acetate extracts (EtOAc) of Linum numidicum Murb. (LN) and Linum trigynum (LT), which have previously been shown to induce G2/M arrest in PC3 prostate cancer cells. We hypothesized that this phenotype results from the direct inhibition of CDK1. To test this hypothesis, a structure-based virtual screening of 78 phytoconstituents identified from LN and LT was conducted against the CDK1/Cks2 and CDK1/cyclin B1/Cks2 complexes. Molecular docking simulations were performed using the Molecular Operating Environment (MOE), with ligand structures optimized and their pharmacokinetic properties evaluated using SwissADME. The CDK1/cyclin B1/Cks2 complex exhibited stronger binding affinities (binding energy < −7.0 kcal/mol) than the CDK1/Cks2 apoenzyme. Notably, several flavonoid glycosides, including 6,4ʹ-dimethoxy-scutellarein-7-neohesperidoside, 8,3ʹ,4ʹ-trihydroxyflavone- 7-O-6(6ʺ-O-p-coumaroyl)-β-d-glucopyranoside, and vicenin- 2 and its isomers, showed higher binding affinities to CDK1 than the known inhibitors NU6102 and dinaciclib. These findings provide the first in silico evidence identifying specific LN and LT metabolites as high-affinity CDK1 ligands, thereby validating the initial hypothesis and providing a strong rationale for the purification and experimental validation of these lead compounds as potential chemotherapeutic agents.