Targeting BCL-2 in Hematological Cancers: Computational Screening of Cucurbitacins as Promising Inhibitors

Background: Disrupting the balance between cell proliferation and death is critical in cancer formation. Increased resistance to apoptosis, which is frequently caused by BCL-2 overexpression, is a critical oncogenic mechanism in many hematologic malignancies, notably lymphoid neoplasias. Overexpression of anti-apoptotic BCL-2 proteins is frequent in many malignancies, prompting the development of BCL-2 inhibitors as therapeutic agents.Methods: In this study, cucurbitacin compounds were screened against BCL-2 using in silico PyRx tool to find strong natural inhibitors for treating hematological malignancies. ADMET-AI web interface was used to analyze ADMET properties of hit compounds. Results: Cucurbitacin O, IIb, K, and H were effective BCL-2 inhibitors, with binding energies ranging from -8.0 to -8.8 kcal/mol, similar to the control compound (-7.9 kcal/mol). These compounds interacted with key amino acid residues in BCL-2. The radial graphs showed that all four compounds had good ADMET characteristics. The compounds have a high probability of being safe for the blood-brain barrier and pose a low risk of hERG channel blockage. Furthermore, they have higher oral bioavailability and adequate water solubility. Their minimal clinical toxicity profiles indicate their potential safety in therapeutic applications.Conclusion: Cucurbitacin O, IIb, K, and H can be employed as BCL-2 inhibitors to manage hematological malignancies. However, further experimental studies are needed to validate these compounds as BCL-2 inhibitors.Keywords: Cancer; Apoptosis; BCL-2; Cucurbitacin compounds; Drug-likeness