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.

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.

Identification of immucillin analogue natural compounds to inhibit Helicobacter pylori MTAN through high throughput virtual screening and molecular dynamics simulation.

ABSTRACT: One in every two humans is having Helicobacter pylori (H. pylori) in stomach causing gastric ulcer. Emergence of several drugs in eliminating H. pylori has paved way for emergence of multidrug resistance in them. This resistance is thriving and thereby necessitating the need of a potent drug. Identifying a potential target for medication is crucial. Bacterial 5'-methylthioadenosine/S-enosyl homocysteine nucleosidase (MTAN) is a multifunctional enzyme that controls seven essential metabolic pathways. It functions as a catalyst in the hydrolysis of the N-ribosidic bond of adenosine-based metabolites: S-adenosylhomocysteine (SAH), 5'-methylthioadenosine (MTA), 5'-deoxyadenosine (5'-DOA), and 6-amino-6-deoxyfutalosine. H. pylori unlike other bacteria and humans utilises an alternative pathway for menaquinone synthesis. It utilises Futosiline pathway for menaquinone synthesis which are obligatory component in electron transport pathway. Therefore, the enzymes functioning in this pathway represent them-self as a point of attack for new medications. We targeted MTAN protein of H. pylori to find out a potent natural hit to inhibit its growth. A comparative analysis was made with potent H. pylori MTAN (HpMTAN) known inhibitor, 5'-butylthio-DADMe-Immucillin-A (BuT-DADMe-ImmA) and ZINC natural subset database. Optimized ligands from the ZINC natural database were virtually screened using ligand based pharmacophore hypothesis to obtain the most efficient and potent inhibitors for HpMTAN. The screened leads were evaluated for their therapeutic likeness. Furthermore, the ligands that passed the test were subjected for MM-GBSA with MTAN to reveal the essential features that contributes selectivity. The results showed that Van der Waals contributions play a central role in determining the selectivity of MTAN. Molecular dynamics (MD) studies were carried out for 100 ns to assess the stability of ligands in the active site. MD analysis showed that binding of ZINC00490333 with MTAN is stable compared to reference inhibitor molecule BuT-DADMe-ImmA. Among the natural inhibitors screened after various docking procedures ZINC00490333 has highest binding score for HpMTAN (- 13.987). The ZINC inhibitor was successful in reproducing the BuT-DADMe-ImmA interactions with HpMTAN. Hence we suggest that ZINC00490333 compound may represent as a good lead in designing novel potent inhibitors of HpMTAN. This in silico approach indicates the potential of this molecule for advancing a further step in gastric ulcer treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00081-2.

Experimental animal models for diabetes and its related complications-a review.

Diabetes mellitus, a very common and multifaceted metabolic disorder is considered as one of the fastest growing public health problems in the world. It is characterized by hyperglycemia, a condition with high glucose level in the blood plasma resulting from defects in insulin secretion or its action and in some cases both the impairment in secretion and also action of insulin coexist. Historically, animal models have played a critical role in exploring and describing malady pathophysiology and recognizable proof of targets and surveying new remedial specialists and in vivo medicines. In the present study, we reviewed the experimental models employed for diabetes and for its related complications. This paper reviews briefly the broad chemical induction of alloxan and streptozotocin and its mechanisms associated with type 1 and type 2 diabetes. Also we highlighted the different models in other species and other animals.