Atomic level and structural understanding of natural ligands inhibiting Helicobacter pylori peptide deformylase through ligand and receptor based screening, SIFT, molecular dynamics and DFT - a structural computational approach

Abstract

Helicobacter pylori is a Gram-negative microaerophilic gastric pathogen, responsible for the cause of peptic ulcer around half of the global population. Although several antibiotics and combination therapies have been employed for H. pylori-related gastric ulcer and cancer regiments, identifying potent inhibitors for specific targets of this bacterium will help assessing better treatment periodicity and methods to eradicate H. pylori. Herein, 1,000,000 natural compounds were virtually screened against Helicobacter pylori Peptide deformylase (HpPDF). Pharmacophore hypotheses were created using ligand and receptor-based pharmacophore modeling of GLIDE. Stringent HTVS and IFD docking protocol of GLIDE predicted leads with stable intermolecular bonds and scores. Molecular dynamics simulation of HpPDF was carried out for 100 ns using GROMACS. Hits ZINC00225109 and ZINC44896875 came up with a glide score of -9.967 kcal/mol and -12.114 kcal/mol whereas; reference compound actinonin produced a glide score of -9.730 kcal/mol. Binding energy values of these hits revealed the involvement of significant Van der Waals and Coulomb forces and the deduction of lipophilic forces that portray the deep hydrophobic residues in the S1pocket of H. pylori. The DFT analysis established the electron density-based features of the molecules and observed that the results correlate with intermolecular docking interactions. Analysis of the MD trajectories revealed the crucial residues involved in HpPDF - ligand binding and the conformational changes in the receptor. We have identified and deciphered the crucial features necessary for the potent ligand binding at catalytic site of HpPDF. The resulting ZINC natural compound hits from the study could be further employed for potent drug development.Communicated by Ramaswamy H. Sarma.

Keywords: ADMET; DFT analysis; HTVS; Helicobacter pylori; MMGBSA; Peptide deformylase; molecular dynamic simulation.