Computational Evaluation of Potent Alkaloids as Promising CDK2 Inhibitors

Abstract

Cyclin-dependent kinase 2 (CDK2) plays a crucial regulatory role in cell-cycle progression, making it an attractive target for anticancer drug development. In this study, six bioactive alkaloids—berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine—were computationally evaluated to identify potent CDK2 inhibitors. The selected molecules, chosen for their well-documented anticancer activities, were subjected to a systematic workflow comprising molecular docking, ADMET prediction, drug-likeness assessment, and environmental toxicity analysis. Molecular docking performed using PyRx and AutoDock Vina revealed that several alkaloids exhibit strong binding affinity toward CDK2, with sanguinarine (–10.3 kcal/mol), evodiamine (–9.8 kcal/mol), and berberine (–9.3 kcal/mol) outperforming the native ligand. Their superior interactions were attributed to favorable hydrogen bonding, electrostatic forces, and extensive hydrophobic contacts within the CDK2 active site. ADMET analysis conducted through SwissADME and ADMETlab 3.0 demonstrated that evodiamine, piperine, and matrine possess balanced pharmacokinetic properties, while berberine and sanguinarine showed moderate oral absorption and acceptable safety profiles. Drug-likeness evaluation indicated full compliance with Lipinski’s rules for all compounds, with evodiamine and matrine exhibiting the highest QED values. Toxicity modeling highlighted moderate risks for certain molecules; however, the potent compounds remained within manageable safety margins. Environmental toxicity assessment further differentiated the compounds based on bioaccumulation and aquatic toxicity potential. Overall, the integrated computational approach identified sanguinarine, evodiamine, and berberine as the most promising CDK2 inhibitors. Their strong binding affinities, supportive ADMET characteristics, and favorable drug-likeness profiles warrant further experimental validation to advance them as potential anticancer therapeutic candidates.