Computational insights into Croton species as sources of CDK4/6 inhibitors for cancer therapy

The search for new anticancer agents has led to the exploration of various botanical resources, with the genus Croton emerging as a promising source of bioactive compounds. CDK4/6 are key cell cycle regulators linked to cancer pathogenesis, and their inhibition has been shown to be effective in treating various cancer cases. Although inhibitors like ribociclib and abemaciclib have demonstrated therapeutic effectiveness, resistance to these drugs invariably arises, requiring the investigation of alternative therapeutic options. In this study, computational screening techniques were used to identify potential dual inhibitors of CDK4/6, aiming to expedite the discovery of alternative anticancer therapeutics from Croton phytochemical data. Prior to structure-based virtual screening, phytochemicals from Croton Spp were identified by an in-depth review of the literature. The chemical space of these phytochemicals was analyzed in comparison with FDA cancer compounds. The resultant druglike molecules were docked into CDK4 (7SJ3) and 6 (5L2T) receptors. The high-ranking ligands were subjected to molecular simulations and HOMO-LUMO energy gap assessments. In chemical space analysis, 56 out of 900 Croton compounds were found to have similar properties to FDA anticancer agents. Molecular docking studies of these 56 compounds revealed that 26 compounds showed high docking scores with CDK6, similar to ribociclib, and six compounds with CDK4, similar to abemaciclib. Cracroson F ( 1 ), Crotocascarin K ( 2 ), Cajucarinolide ( 3 ), and Isocajucarinolide ( 4 ) were predicted as the dual inhibitors showing docking scores for CDK4 (-11, -11, -10.7, and -10.6 kcalmol -1 , respectively) and CDK6 (-9.1, -9.4, -8.4, and -9.6 kcalmol -1 , respectively). Compounds 1 and 3 showed stability in 200 ns MD simulations, generating hydrophobic, ionic, and hydrogen interactions with an ideal radius of gyration and root mean square deviations and fluctuations (RMSD and RMSF). DFT calculation revealed that 3 (ΔE = 3.522 eV) was more reactive than 1 (ΔE = 3.648 eV) due to its HOMO-LUMO gap, though both were inferior to the standards. These two compounds were predicted to have acceptable pharmacokinetics, off-target, and toxicity profiles, indicating their potential as drug candidates. The in silico study thus identified promising Croton-lead compounds with potential anticancer properties, requiring further experimental (in vitro and in vivo) evaluation.