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Search for Potential Inducible Nitric Oxide Synthase Inhibitors with Favorable ADMET Profiles for the Therapy of Helicobacter pylori Infections

[ Vol. 19 , Issue. 30 ]

Author(s):

Ricardo Pereira Rodrigues*, Juliana Santa Ardisson, Rita de Cássia Ribeiro Gonçalves, Tiago Branquinho Oliveira, Vinicius Barreto da Silva, Daniel Fábio Kawano and Rodrigo Rezende Kitagawa   Pages 2795 - 2804 ( 10 )

Abstract:


Background: Helicobacter pylori is a gram-negative bacterium related to chronic gastritis, peptic ulcer and gastric carcinoma. During its infection process, promotes excessive inflammatory response, increasing the release of reactive species and inducing the production of pro-inflammatory mediators. Inducible Nitric Oxide Synthase (iNOS) plays a crucial role in the gastric carcinogenesis process and a key mediator of inflammation and host defense systems, which is expressed in macrophages induced by inflammatory stimuli. In chronic diseases such as Helicobacter pylori infections, the overproduction of NO due to the prolonged induction of iNOS is of major concern.

Objectives: In this sense, the search for potential iNOS inhibitors is a valuable strategy in the overall process of Helicobacter pylori pathogeny.

Methods: In silico techniques were applied in the search of interesting compounds against Inducible Nitric Oxide Synthase enzyme in a chemical space of natural products and derivatives from the Analyticon Discovery databases.

Results: The five compounds with the best iNOS inhibition profile were selected for activity and toxicity predictions. Compound 9 (CAS 88198-99-6) displayed significant potential for iNOS inhibition, forming hydrogen bonds with residues from the active site and an ionic interaction with heme. This compound also displayed good bioavailability and absence of toxicity/or from its probable metabolites.

Conclusion: The top-ranked compounds from the virtual screening workflow show promising results regarding the iNOS inhibition profile. The results evidenced the importance of the ionic bonding during docking selection, playing a crucial role in binding and positioning during ligand-target selection for iNOS.

Keywords:

Molecular docking, Virtual screening, Helicobacter pylori, Inducible nitric oxide synthase, Natural product research, Gastric carcinogenesis.

Affiliation:

Graduate Program in Pharmaceutical Sciences, Health Sciences Center - CCS, Federal University of Espirito Santo - UFES, Marechal Campos Av., 1468, Vitoria 29043-900, ES, Graduate Program in Pharmaceutical Sciences, Health Sciences Center - CCS, Federal University of Espirito Santo - UFES, Marechal Campos Av., 1468, Vitoria 29043-900, ES, Graduate Program in Pharmaceutical Sciences, Health Sciences Center - CCS, Federal University of Espirito Santo - UFES, Marechal Campos Av., 1468, Vitoria 29043-900, ES, Department of Pharmacy, Federal University of Sergipe (UFS-SE), Av. Marechal Rondon s/n, Jd. Rosa Elze, Sao Cristovao 49100-000, SE, Department of Biomedicine and Pharmacy, Pontifical Catholic University of Goiás, 74605-140 Goiania-GO, Faculty of Pharmaceutical Sciences, University of Campinas, Rua Candido Portinari 200, 13083-871 Campinas- SP, Graduate Program in Pharmaceutical Sciences, Health Sciences Center - CCS, Federal University of Espirito Santo - UFES, Marechal Campos Av., 1468, Vitoria 29043-900, ES

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