In Silico Evaluation of Vitamin D3 as a Dual Inhibitor of CDK2 and Bcl-2 in Colorectal Cancer

Background: Vitamin D3 (cholecalciferol) has garnered growing interest for its potential anticancer properties. Epidemiological and preclinical studies suggest an inverse correlation between vitamin D3 levels and the incidence of colorectal cancer (CRC). However, the precise molecular mechanisms and direct targets through which vitamin D3 exerts anticancer effects remain inadequately characterized. Aim: This study aims to investigate the dual-targeting potential of vitamin D3 against two key oncogenic proteins involved in CRC pathogenesis: cyclin-dependent kinase 2 (CDK2), a critical regulator of cell cycle progression, and B-cell lymphoma 2 (Bcl-2), an anti-apoptotic protein implicated in tumor survival. Method: Molecular docking was conducted to assess the binding affinity of vitamin D3 to CDK2 and Bcl-2. MD simulations evaluated the stability of the docked complexes over time. ADMET analysis was performed to predict the pharmacokinetic and safety profile of vitamin D3. Results: Docking analysis revealed strong binding affinities of vitamin D3 to both CDK2 (-9.5 kcal/mol) and Bcl-2 (-8.2 kcal/mol), suggesting stable interactions at functionally critical regions, namely the ATP-binding site of CDK2 and the BH3-binding groove of Bcl-2. Molecular dynamics simulations confirmed the conformational stability and sustained interactions of vitamin D3 with both targets throughout the simulation period. ADMET predictions indicated favorable oral bioavailability, low toxicity, and acceptable absorption and distribution characteristics, although limitations were noted in solubility and high plasma protein binding. Conclusion: This study provides the first computational evidence that vitamin D3 may exert anticancer effects in colorectal cancer via dual mechanisms—cell cycle arrest through CDK2 inhibition and apoptosis induction through Bcl-2 modulation. These findings offer a novel perspective on the therapeutic repositioning of vitamin D3 as a multi-target agent in CRC management and warrant further validation through in vitro and in vivo studies.