Flavonoid and Organosulphur Phytoconstituents From Allium Sativum Inhibits Antiapoptotic Protein Bcl-2: A Computational Molecular Modeling Study

ABSTRACT: PURPOSE Apoptosis resistance to anticancer treatments can occur due to over-expression of Bcl-2 anti-apoptotic proteins. Studies have shown the use of Allium sativum (garlic) as a herbal supplement among cancer patients. In this study, the inhibitory activity of phytochemicals from Allium sativum against Bcl-2 anti-apoptotic protein was demonstrated using a computational technique.

METHODS

Identified phytoconstituents from A. sativum were docked in receptor grid generated active sites of Bcl-2 (PDB-ID: 4AQ3) protein using the Glide-Ligand docking tool of Schrödinger Maestro 12.5. Receptor-ligand complex pharmacophore models were generated using the PHASE module, and the binding free energy of the complex was calculated using the MM-GBSA Prime panel. Potential lead compounds were screened for drug likeness using the Lipinski rule of five (RO5) and Veber rule. Absorption, distribution, metabolism, excretion, and toxicity (ADME/T) predictions of the leads were carried out using the PROTOX-II tool. Induced fit docking simulation was performed on the top ranked hit compound.

RESULTS

Extra precision docking results showed that myricetin, kaempferol, and apigenin (flavonoid); α and β-phellandrene (cyclic monoterpene); 3-vinyl-4H-1,2-dithiin, 3-vinyl-1,2-dithiin and 2-vinyl-4H-1,3-dithiine (organosulphur) were ranked highest, with docking scores range from -6.00 to -3.78 kcal/mol compared with -3.62 kcal/mol demonstrated by co-crystallized ligand. Apigenin (CID: 5280443), 3-vinyl-1,2-dithiin (CID: 10219489), and 3-vinyl-4H-1,2-dithiin (CID: 150636) were identified as the top three lead compounds with free binding energies of -33.83, -30.36, and -29.70 kcal/mol respectively. The identified lead compounds from A. sativum were in accordance with RO5 and Veber rule with good oral bio-availability and ADME/T profile. Similar to the co-crystallized ligand, apigenin interacted with important active site amino acid residues like Try 67, Asp 70, Leu 96, Arg 105, Ala 108 among others.

CONCLUSION

Some bioactive phytochemicals from A. sativum can be explored for development toward inhibition of antiapoptotic protein Bcl-2 in apoptosis resistance to anticancer treatments.

SUBMITTER: Ibrahim M 

PROVIDER: S-EPMC9906517 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature