Abstract

Background: Quercetin and apigenin are a new class of drug targets for Helicobacter pylori D-alanine- D-alanine ligase (HpDdl). However, their clinical use is limited by its oral bioavailability and hence requires its molecular modification. The present study is an attempt to investigate the insights of competitive inhibition of these compounds.

Methods: In silico ligand-protein interaction was carried out, predicting molecular recognition, explicating the binding modes and its binding affinity. Molecular Dynamic (MD) simulations were also performed and their free binding energies were evaluated. Additionally, the Density Functional Theory (DFT) analysis was carried out.

Result: The docking simulation showed quercetin having a rerank score of -67.97 compared to -57.75 of apigenin and -45.04 of ATP molecule respectively. The interaction energy analysis revealed quercetin having a favorable total interaction energy of -101.45 kJ mol-1 compared to -91.67 kJ mol-1 and -70.23 kJ mol-1 for apigenin and ATP molecule, respectively. The Root Mean Squared Deviation (RMSD) plot from the MD simulation clearly explains the variations of the Hpddl enzyme and protein-ligand binding complexes. Additionally, the Density Functional Theory (DFT) analysis revealed the HOMO and LUMO favourable energies of quercetin and apigenin.

Conclusion: The study reveals the insights on quercetin and apigenin showing competitive inhibition with ATP. The free binding energy calculation confirms the stable binding energy. The MD simulation revealed the conformation changes and the stability of the docked complex. The molecular orbital’s analysis on HOMO and LUMO energies depicts the regions which might favour electrophilic attack and nucleophilic attack.

Keywords: Flavonoids, D-alanine, molecular docking, molecular dynamics, Helicobacter pylori, ATP binding site.

Graphical Abstract