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In silico design and in vitro assessment of anti-Helicobacter pylori compounds as potential small-molecule arginase inhibitors

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Abstract

Related to a variety of gastrointestinal disorders ranging from gastric ulcer to gastric adenocarcinoma, the infection caused by the gram-negative bacteria Helicobacter pylori (H. pylori) poses as a great threat to human health; hence, the search for new treatments is a global priority. The H. pylori arginase (HPA) protein has been widely studied as one of the main virulence factors of this bacterium, being involved in the prevention of nitric oxide-mediated bacterial cell death, which is a central component of innate immunity. Given the growing need for the development of new drugs capable of combating the infection by H. pylori, the present work describes the search for new HPA inhibitors, using virtual screening techniques based on molecular docking followed by the evaluation of the proposed modes of interaction at the HPA active site. In vitro studies of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), followed by cytotoxicity activity in gastric adenocarcinoma and non-cancer cells, were performed. The results highlighted compounds 6, 11, and 13 as potential inhibitors of HPA; within these compounds, the results indicated 13 presented an improved activity toward H. pylori killing, with MIC and MBC both at 64 µg/mL. Moreover, compound 13 also presented a selectivity index of 8.3, thus being more selective for gastric adenocarcinoma cells compared to the commercial drug cisplatin. Overall, the present work demonstrates the search strategy based on in silico and in vitro techniques is able to support the rational design of new anti-H. pylori drugs.

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Abbreviations

ADME:

Absorption, distribution, metabolism, and excretion

AGS:

Gastric adenocarcinoma

ATCC:

American type culture collection

AUC:

Areas under the ROC curves

BHI:

Brain heart infusion

DSV:

Discovery studio visualizer

EF 1%:

Enrichment factor of 1%

H. pylori :

Helicobacter pylori

HPA:

Helicobacter pylori arginase

IC50 :

Half maximal inhibitory concentration

MBC:

Minimum bactericidal concentration

MIC:

Minimum inhibitory concentration

NO:

Nitric oxide

NOS:

Nitric oxide synthase

PDB:

Protein data bank

QSAR:

Quantitative structure–activity relationship

ROC:

Receiver operating characteristic

SI:

Selectivity indexes

TP:

Tanimoto prioritization

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Acknowledgements

The authors thank the University of Sao Paulo, in the person of Prof. Dr. Ivone Carvalho, for the use of the MetaCore platform from Clarivate Analytics in the prediction of pharmacokinetic endpoints. The authors thank the “Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, grant 2018/08585-1: D.F.K.)” and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grant 309802/2020-2: M.L.)” for the financial support. This study was financed in part by the “Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES, Finance Code 001; Project 39-P-4763/2018: A.T.F.D.; grants 88882.385410/2019-01: J.R.P.O.B.; 88887.643019/2021-00: R.R.K.; 88887.643019/2021-00: J.P.O.G.; 88887.512993/2020-00: R.P.R.)

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, University of Campinas – UNICAMP, Rua Cândido Portinari 200, Campinas, SP, 13083-871, Brazil

    Ana Thereza Fiori-Duarte, João Paulo de Oliveira Guarnieri, Marcelo Lancellotti & Daniel Fábio Kawano

  2. Department of Pharmaceutical Sciences, Health Sciences Center - CCS, Federal University of Espírito Santo - UFES, Av. Marechal Campos 1468, Vitoria, ES, 29047-105, Brazil

    Jessica Rodrigues Pereira de Oliveira Borlot, Ricardo Pereira Rodrigues & Rodrigo Rezende Kitagawa

  3. Institute of Chemistry, University of Campinas – UNICAMP, Rua Josué de Castro S/N, Campinas, SP, Brazil

    Daniel Fábio Kawano

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  1. Ana Thereza Fiori-Duarte
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Fiori-Duarte, A.T., de Oliveira Guarnieri, J.P., de Oliveira Borlot, J.R.P. et al. In silico design and in vitro assessment of anti-Helicobacter pylori compounds as potential small-molecule arginase inhibitors. Mol Divers 26, 3365–3378 (2022). https://doi.org/10.1007/s11030-021-10371-8

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