Quercetin-induced apoptosis in HepG2 cells and identification of quercetin derivatives as potent inhibitors for Caspase-3 through computational methods

• Published in: Structural chemistry 2022-12, Vol.33 (6), p.1867-1893
• Main Authors: Ramachandran, Balajee, Jeyarajpandian, Chitra, Jeyaseelan, Jeba Mercy, Prabhu, Dhamodharan, Rajamanikandan, Sundaraj, Boomi, Pandi, Venkateswari, Ramachandra, Jeyakanthan, Jeyaraman
• Format: Article
• Language: English
• Subjects: Affinity; Analysis; Anticancer properties; Antioxidants; Apoptosis; Aromatic compounds; Binding; Bioflavonoids; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Dexmedetomidine; Flavones; Flavonoids; Hydrogen; Hydrogen bonds; Liver cancer; Methods; Molecular docking; Molecular dynamics; Molecular orbitals; Original Research; Pharmacology; Physical Chemistry; Rankings; Theoretical and Computational Chemistry; Water chemistry
• ISSN: 1040-0400; 1572-9001
• DOI: 10.1007/s11224-022-01933-z

Quercetin is a bioflavonoid which possesses immune-enhancing activity, anti-inflammatory, antioxidant properties and considered effective against various cancers. In the present study, quercetin has been extracted from Ocimum basilicum and was used to evaluate its anticancer activity against human liver cancer cell lines (HepG2) by assessing cell viability (MTT) and variations in nuclear morphology (AO/EtBr dual staining) during apoptosis. Since Caspase-3 enables the activation of cascade which is responsible for apoptosis, their effects were also investigated using computational approaches like molecular docking, molecular dynamics, covalent docking, ADME prediction, DFT approaches, and pharmacophore modeling besides identifying the binding affinity, stability, drug likeliness properties of top-ranked compounds. Amount of quercetin extracted from O. basilicum leaves was found to be 0.82 mg with the retention time of 2.827 min. Quercetin showed dose-dependent anticancer activity against HepG2 cells with IC 50 value 50 µg/mL due to apoptosis that could have been mediated by Caspase-3 activity. Computational analysis of quercetin inhibiting Caspase-3 showed better binding affinity of compounds ChEMBL_38464, ChEMBL_501025, and ChEMBL_525002 and no violations were observed in the Lipinski Rule of 5. The molecular dynamics simulation evidenced the presence of water molecule in the catalytic site stabilizes the complex. The DFT analysis also explored that the identified compounds have the least HOMO–LUMO gap. The identified compounds also exhibit the pharmacophoric features such as hydrogen bond acceptor, hydrogen bond donor, aromatic ring, and hydrophobic features. Moreover, the study indicates the importance of water molecule in the catalytic site which may suppress the growth of tumor cells which could assist in the selection of potential leads for further analysis against liver cancer.