Molecular docking, pharmacophore based virtual screening and molecular dynamics studies towards the identification of potential leads for the management of H. pylori

Abstract

The enzyme pantothenate synthetase panC is one of the potential new antimicrobial drug targets, but it is poorly characterized in H. pylori. H. pylori infection can cause gastric cancer and the management of H. pylori infection is crucial in various gastric ulcers and gastric cancer. The current study describes the use of innovative drug discovery and design approaches like comparative metabolic pathway analysis (Metacyc), exploration of database of essential genes (DEG), homology modelling, pharmacophore based virtual screening, ADMET studies and molecular dynamics simulations in identifying potential lead compounds for the H. pylori specific panC. The top ranked virtual hits STOCK1N-60270, STOCK1N-63040, STOCK1N-44424 and STOCK1N-63231 can act as templates for synthesis of new H. pylori inhibitors and they hold a promise in the management of gastric cancers caused by H. pylori.

Fig. 1. Sequence alignment of model and template.

Fig. 2. Structural alignment of homology model and template structure (A) Cα backbone alignment; (B) all atom alignment.

Fig. 3. Structure validation parameter Ramachandran plot and ProSa Z score of model structure.

Fig. 4. PanC binding site residues predicted by site finder module of MOE.

Fig. 5. The binding pose and molecular interactions of inhibitor 63 into the active site of the model structure of the PanC.

Fig. 6. 3D-pharmacophore models of the top docked hit 63 into the active site of the homology model of the PanC.

Fig. 7. Schematic representation of the virtual screening protocol.

Fig. 8. The binding pose of top hits at binding site, (A) STOCK1IN 63040; (B) STOCK1IN 44424; (C) STOCK1IN 63231 and; (D) STOCK1IN 60270.

Fig. 9. The docked conformers of ligand 63 (magenta) and top virtual hit STOCK1N-60270 (green) at the binding site.

Fig. 10. Structures of the top virtual hits.

Fig. 11. RMSD for panC (A) the backbone atoms and (B) the atoms of virtual hits.

Fig. 12. RMS fluctuations in the backbone atoms during the MD simulations.

Fig. 13. Hydrogen bonds formed with the chosen virtual hits during entire MD simulation (A) 44424; (B) 60270; (C) 63040; and (D) 63231.

Fig. 14. Energy evaluation between the protein and the hit molecules. (A) The short range coulombic interaction energy; (B) the short range Lennard-Jones interaction energy.