Molecular Docking of Anti Helicobacter pylori Antibiotics and Proton Pump Inhibitor: A Single Center Survey

Helicobacter pylorus (H. pylori) is a deadly bacterium responsible for significant worldwide Gastric Cancer (GC) related mortality. The present study aimed to screen all the anti-microbial drugs used to eradicate H .pylori infection and to identify the most efficient drug by using computational methods through molecular docking analysis. The 3-D structure of protein chorismate synthase of H. pylori was downloaded from the Protein data bank (PDB) online browser. The x-ray crystallography structures of 13 common drugs used against H.pylori infection were also downloaded from the drug bank. We screened all 13 common drugs through molecular docking to know the most efficient binding interaction between the diverse ligand-protein complexes. The results were further compared with clinical survey data from the patients with diverse gastrointestinal H. pylori infected cases. Among the screened compounds, by in-silico approach we found that fluoroquinolone (FLRQ) and tetracycline (TET) manifested more significant interactions with chorismate synthase (CS) protein along with binding energies of -9.2 and -8.1 kcal/mole respectively. Further, the drugs were also corroborated with the survey data from patients with varied gastrointestinal disorders in our study. With this computational study, we could find FLRQ and TET may be the most efficient drug for H. pylori treatment, which can be tried in case of anti H. Pylori treatment failure due to resistance. Hence, effective inter-analysis between the experimental and computational approaches is crucial to build up a strong inhibitor.

Chorismate synthase mediates cerebral malaria pathogenesis by eliciting salicylic acid-dependent autophagy response in parasite

ABSTRACTCerebral malaria caused by Plasmodium falciparum is the severest form of the disease resulting in the morbidity of a huge number of people worldwide. Development of effective curatives is essential in order to overcome the fatality of cerebral malaria. Earlier studies have shown the presence of salicylic acid (SA) in malaria parasite P. falciparum, which plays a critical role in the manifestation of cerebral malaria. Further, the application of SA for the treatment of acute symptoms in cerebral malaria increases the activity of iNOS leading to severe inflammation-mediated death, also called as Reye's syndrome. Therefore, modulation of the level of SA might be a novel approach to neutralize the symptoms of cerebral malaria. The probable source of parasite SA is the shikimate pathway, which produces chorismate, a precursor to aromatic amino acids and other secondary metabolites like SA in the parasite. In this work, we performed the immunological, pathological and biochemical studies in mice infected with chorismate synthase knocked-out Plasmodium berghei ANKA, which does not produce SA. Fewer cerebral outcomes were observed as compared to the mice infected with wild-type parasite. The possible mechanism behind this protective effect might be the hindrance of SA-mediated induction of autophagy in the parasite, which helps in its survival in the stressed condition of brain microvasculature during cerebral malaria. The absence of SA leading to reduced parasite load along with the reduced pathological symptoms contributes to less fatality outcome by cerebral malaria.

In silico screening of natural products targeting chorismate synthase

Introduction: Chorismate synthase catalyzes the final step in shikimate acid pathway involved in synthesis of aromatic compounds in bacteria.This enzyme can be a possible molecular target for design of antibiotics. Materials and Methods: Homology modeling and molecular dockingwere performed to screen about one hundred natural compounds in order to find inhibitors of enzymes as a possible new target. A model wasbuilt by SWISS-MODEL and its quality was assessed by ERRAT, ProSA, Rampage and MolProbity servers. Docking experiments were performedand pharmacokinetics and toxicities were studied by admetSAR. Results: The predicted model was reliable to be used in docking experiments.Amentoflavone had the highest binding affinity of -10.0 Kcal/mol. Probabilities indicated that rotenone may inhibit P-glycoprotein I, hinokiflavone and silybin may inhibit P-glycoprotein II, while taspine acts on both types of P-glycoproteins. Amentofalavone, hinokiflavone, rotenone and silybin have a probability of inhibiting cytochromes that are involved in oxidation stage of metabolism. Conclusions: These compounds had binding affinities towards FMN binding site of the enzyme model and may be considered in the research for new antibacterial agents but only when their drug interactions are fully investigated.

New inhibitors of chorismate synthase present antifungal activity against Paracoccidioides brasiliensis

Aim: A structural model of chorismate synthase (CS) from the pathogenic fungus Candida albicans was used for virtual screening simulations. Methods: Docking, molecular dynamics, cell growth inhibition and protein binding assays were used for search and validation. Results: Two molecules termed CS8 and CaCS02 were identified. Further studies of the minimal inhibitory concentration demonstrated fungicidal activity against Paracoccidioides brasiliensis with a minimal inhibitory concentration and minimal fungicidal concentration of 512 and 32 μg·ml-1 for CS8 and CaCS02, respectively. In addition, CaCS02 showed a strong synergistic effect in combination with amphotericin B without cytotoxic effects. In vitro studies using recombinant CS from P. brasiliensis showed IC50 of 29 μM for CaCS02 supporting our interpretation that inhibition of CS causes the observed fungicidal activity.

Promising New Antifungal Treatment Targeting Chorismate Synthase from Paracoccidioides brasiliensis

ABSTRACT Paracoccidioidomycosis (PCM), caused by Paracoccidioides, is a systemic mycosis with granulomatous character and a restricted therapeutic arsenal. The aim of this work was to search for new alternatives to treat largely neglected tropical mycosis, such as PCM. In this context, the enzymes of the shikimate pathway constitute excellent drug targets for conferring selective toxicity because this pathway is absent in humans but essential for the fungus. In this work, we have used a homology model of the chorismate synthase (EC 4.2.3.5) from Paracoccidioides brasiliensis (PbCS) and performed a combination of virtual screening and molecular dynamics testing to identify new potential inhibitors. The best hit, CP1, successfully adhered to pharmacological criteria (adsorption, distribution, metabolism, excretion, and toxicity) and was therefore used in in vitro experiments. Here we demonstrate that CP1 binds with a dissociation constant of 64 ± 1 μM to recombinant chorismate synthase from P. brasiliensis and inhibits enzymatic activity, with a 50% inhibitory concentration (IC50) of 47 ± 5 μM. As expected, CP1 showed no toxicity in three cell lines. On the other hand, CP1 reduced the fungal burden in lungs from treated mice, similar to itraconazole. In addition, histopathological analysis showed that animals treated with CP1 displayed less lung tissue infiltration, fewer yeast cells, and large areas with preserved architecture. Therefore, CP1 was able to control PCM in mice with a lower inflammatory response and is thus a promising candidate and lead structure for the development of drugs useful in PCM treatment.