In silico approach towards the identification of potential inhibitors from Curcuma amada Roxb against H. pylori: ADMET screening and molecular docking studies

Introduction: The present study attempts to identify potential targets of H. pylori for novel inhibitors from therapeutic herb, mango ginger (Curcuma amada Roxb.). Methods: Crystal structure of all the selected drug targets obtained from Protein Data Bank (PDB) were subjected to molecular docking against a total of 130 compounds (found to have biological activity against H. pylori) were retrieved from public databases. Compounds with good binding affinity were selected for Prime MM-GBSA rescoring and molecular dynamics (MD) simulation. Final list of compounds were taken for ADMET predictions. Results: Based on binding affinity denoted by glide score and ligand efficiency, mango ginger compounds were found selective to shikimate kinase and type II dehydroquinase through hydrogen bonding and salt bridge interactions. Stability of the interactions and free energy calculations by Prime MM-GBSA results confirmed the affinity of mango ginger compounds towards both shikimate kinase and type II dehydroquinase. From the above results, 15 compounds were calculated for ADMET parameters, Lipinski’s rule of five, and the results were found promising without any limitations. MD simulations identified gentisic acid as hit compound for shikimate kinase of H. pylori. Conclusion: Current study could identify the in silico potential of mango ginger compounds against shikimate kinase and type II dehydroquinase targets for H. pylori infections and are suitable for in vitro and in vivo evaluation.

QM/MM simulations identify the determinants of catalytic activity differences between type II dehydroquinase enzymes

Multiscale simulations pinpoint specific interactions responsible for differences in stabilization of key reacting species in two recognized targets for antibiotic development.

Structure of type II dehydroquinase fromPseudomonas aeruginosa

Pseudomonas aeruginosacauses opportunistic infections and is resistant to most antibiotics. Ongoing efforts to generate much-needed new antibiotics include targeting enzymes that are vital forP. aeruginosabut are absent in mammals. One such enzyme, type II dehydroquinase (DHQase), catalyzes the interconversion of 3-dehydroquinate and 3-dehydroshikimate, a necessary step in the shikimate pathway. This step is vital for the proper synthesis of phenylalanine, tryptophan, tyrosine and other aromatic metabolites. The recombinant expression, purification and crystal structure of catalytically active DHQase fromP. aeruginosa(PaDHQase) are presented. Cubic crystals belonging to space groupF23, with unit-cell parametersa=b=c= 125.39 Å, were obtained by vapor diffusion in sitting drops and the structure was refined to anRfactor of 16% at 1.74 Å resolution. PaDHQase is a prototypical type II DHQase with the classical flavodoxin-like α/β topology.