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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

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

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

Volume 19, Issue 30, 2019

Page: [2795 - 2804] Pages: 10

DOI: 10.2174/1568026619666191112105650

Price: $65

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.

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[1]
Sugano, K.; Tack, J.; Kuipers, E.J.; Graham, D.Y.; El-Omar, E.M.; Miura, S.; Haruma, K.; Asaka, M.; Uemura, N.; Malfertheiner, P. Kyoto global consensus report on Helicobacter pylori gastritis. Gut, 2015, 64(9), 1353-1367.
[http://dx.doi.org/10.1136/gutjnl-2015-309252] [PMID: 26187502]
[2]
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
[http://dx.doi.org/10.1002/ijc.29210] [PMID: 25220842]
[3]
Wroblewski, L.E.; Peek, R.M., Jr; Wilson, K.T. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin. Microbiol. Rev., 2010, 23(4), 713-739.
[http://dx.doi.org/10.1128/CMR.00011-10] [PMID: 20930071]
[4]
Chen, A.L. Role of the Helicobacter pylori-induced inflammatory response in the development of gastric cancer. J. Cell. Biochem., 2014, 114(3), 491-497.
[http://dx.doi.org/10.1002/jcb.24389.]
[5]
Huang, Z.; Fu, J.; Zhang, Y. Nitric oxide donor-based cancer therapy: advances and prospects. J. Med. Chem., 2017, 60(18), 7617-7635.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01672] [PMID: 28505442]
[6]
de Oliveira, G.A.; Cheng, R.Y.S.; Ridnour, L.A.; Basudhar, D.; Somasundaram, V.; McVicar, D.W.; Monteiro, H.P.; Wink, D.A. Inducible nitric oxide synthase in the carcinogenesis of gastrointestinal cancers. Antioxid. Redox Signal., 2017, 26(18), 1059-1077.
[http://dx.doi.org/10.1089/ars.2016.6850] [PMID: 27494631]
[7]
Alderton, W.K.; Cooper, C.E.; Knowles, R.G. Nitric oxide synthases: structure, function and inhibition. Biochem. J., 2001, 357(Pt 3), 593-615.
[http://dx.doi.org/10.1042/bj3570593] [PMID: 11463332]
[8]
McMillan, K.; Adler, M.; Auld, D.S.; Baldwin, J.J.; Blasko, E.; Browne, L.J.; Chelsky, D.; Davey, D.; Dolle, R.E.; Eagen, K.A.; Erickson, S.; Feldman, R.I.; Glaser, C.B.; Mallari, C.; Morrissey, M.M.; Ohlmeyer, M.H.J.; Pan, G.; Parkinson, J.F.; Phillips, G.B.; Polokoff, M.A.; Sigal, N.H.; Vergona, R.; Whitlow, M.; Young, T.A.; Devlin, J.J. Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. Proc. Natl. Acad. Sci. USA, 2000, 97(4), 1506-1511.
[http://dx.doi.org/10.1073/pnas.97.4.1506] [PMID: 10677491]
[9]
Fedorov, R.; Hartmann, E.; Ghosh, D.K.; Schlichting, I. Structural basis for the specificity of the nitric-oxide synthase inhibitors W1400 and Nomega-propyl-L-Arg for the inducible and neuronal isoforms. J. Biol. Chem., 2003, 278(46), 45818-45825.
[http://dx.doi.org/10.1074/jbc.M306030200] [PMID: 12954642]
[10]
Peterson, D.A.; Peterson, D.C.; Archer, S.; Weir, E.K. The non specificity of specific nitric oxide synthase inhibitors. Biochem. Biophys. Res. Commun., 1992, 187(2), 797-801.
[http://dx.doi.org/10.1016/0006-291X(92)91266-S] [PMID: 1382421]
[11]
Rodrigues, T.; Reker, D.; Schneider, P.; Schneider, G. Counting on natural products for drug design. Nat. Chem., 2016, 8(6), 531-541.
[http://dx.doi.org/10.1038/nchem.2479] [PMID: 27219696]
[12]
MarvinSketch Version 16.. Drawing Module. Developed by ChemAxon, 2016.
[13]
Dalby, A.; Nourse, J.G.; Hounshell, W.D.; Gushurst, A.K.I.; Grier, D.L.; Leland, B.A.; Laufer, J. Description of several chemical structure file formats used by computer programs developed at molecular design limited. J. Chem. Inf. Model., 1992, 32, 244-255.
[http://dx.doi.org/10.1021/ci00007a012]
[14]
Hanwell, M.D.; Curtis, D.E.; Lonie, D.C.; Vandermeersch, T.; Zurek, E.; Hutchison, G.R. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform., 2012, 4(1), 17.
[http://dx.doi.org/10.1186/1758-2946-4-17] [PMID: 22889332]
[15]
Hawkins, P.C.; Skillman, A.G.; Warren, G.L.; Ellingson, B.A.; Stahl, M.T. Conformer generation with OMEGA: algorithm and validation using high quality structures from the Protein Databank and Cambridge Structural Database. J. Chem. Inf. Model., 2010, 50(4), 572-584.
[http://dx.doi.org/10.1021/ci100031x] [PMID: 20235588]
[16]
Hawkins, P.C.D.; Skillman, A.G.; Warren, G.L.; Ellingson, B.A.; Stahl, M.T. ROCS 3.2.1.4: OpenEye Scientific Software.Santa Fe, NM, 2014.
[17]
EON 2.2.0.5:. OpenEye Scientific Software, Santa Fe, NM
[18]
Filimonov, D.A.; Druzhilovskiy, D.S.; Lagunin, A.A.; Gloriozova, T.A.; Rudik, A.V.; Dmitriev, A.V.; Pogodin, P.V.; Poroikov, V.V. Computer-aided prediction of biological activity spectra for chemical compounds: opportunities and limitations. Biomed. Chem. Res. Methods, 2018, 1
[http://dx.doi.org/10.18097/BMCRM00004]
[19]
Greene, N.; Judson, P.N.; Langowski, J.J.; Marchant, C.A. Knowledge-based expert systems for toxicity and metabolism prediction: DEREK, StAR and METEOR. SAR QSAR Environ. Res., 1999, 10(2-3), 299-314.
[http://dx.doi.org/10.1080/10629369908039182] [PMID: 10491855]
[20]
Verdonk, M.L.; Cole, J.C.; Hartshorn, M.J.; Murray, C.W.; Taylor, R.D. Improved protein-ligand docking using GOLD. Proteins, 2003, 52(4), 609-623.
[http://dx.doi.org/10.1002/prot.10465] [PMID: 12910460]
[21]
Kirchmair, J.; Markt, P.; Distinto, S.; Schuster, D.; Spitzer, G.M.; Liedl, K.R.; Langer, T.; Wolber, G. The Protein Data Bank (PDB), its related services and software tools as key components for in silico guided drug discovery. J. Med. Chem., 2008, 51(22), 7021-7040.
[http://dx.doi.org/10.1021/jm8005977] [PMID: 18975926]
[22]
Jones, G.; Willett, P.; Glen, R.C.; Leach, A.R.; Taylor, R. Development and validation of a genetic algorithm for flexible. J. Mol. Biol., 1997, 267(3), 727-748.
[http://dx.doi.org/10.1006/jmbi.1996.0897]
[23]
Bergström, C.A.S.; Haeberlein, M.; Norinder, U. Computational Absorption Prediction; Drug Bioavailability, 2009.
[24]
Markt, P.; Petersen, R.K.; Flindt, E.N.; Kristiansen, K.; Kirchmair, J.; Spitzer, G.; Distinto, S.; Schuster, D.; Wolber, G.; Laggner, C.; Langer, T. Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening. J. Med. Chem., 2008, 51(20), 6303-6317.
[http://dx.doi.org/10.1021/jm800128k] [PMID: 18821746]
[25]
Kearnes, S.; Pande, V. ROCS-derived features for virtual screening. J. Comput. Aided Mol. Des., 2016, 30(8), 609-617.
[http://dx.doi.org/10.1007/s10822-016-9959-3] [PMID: 27624668]
[26]
Kerns, E.H.; Di, L. Drug-like properties: concepts, structure, design, and methods. from ADME to toxicity optimization, 1st ed; Academic Press: San Diego, 2008.
[27]
Martinat, C.; Amar, C.; Dansette, P.M.; Leclaire, J.; Lopez-Garcia, P.; Cao, T.D.; N’Guyen, H.N.; Mansuy, D. In vitro metabolism of isaxonine phosphate: formation of two metabolites, 5-hydroxyisaxonine and 2-aminopyrimidine, and covalent binding to microsomal proteins. Eur. J. Pharmacol., 1992, 228(1), 63-71.
[PMID: 1397069]
[28]
Kanerva, L.; Elsner, P.; Wahlberg, J.E.; Maibach, H. Handbook of occupational dermatology; Springer: Berlin, 2000.
[http://dx.doi.org/10.1007/978-3-662-07677-4]
[29]
US Environmental Protection Agency. Guideline for human exposure assessment. Risk Assess. Forum, 2016, 1-199.
[30]
Barratt, M.D.; Basketter, D.A. Possible origin of the skin sensitization potential of isoeugenol and related compounds. (I). Preliminary studies of potential reaction mechanisms. Contact Dermat., 1992, 27(2), 98-104.
[http://dx.doi.org/10.1111/j.1600-0536.1992.tb05217.x] [PMID: 1395636]
[31]
Mehta, R.; Chan, K.; Lee, O.; Tafazoli, S.; O’Brien, P.J. Drug-Associated Mitochondrial Toxicity.. 2008.
[http://dx.doi.org/10.1002/9780470372531.ch3]
[32]
Powell, C.J.; Connolly, A.K. The site specificity and sensitivity of the rat liver to butylated hydroxytoluene-induced damage. Toxicol. Appl. Pharmacol., 1991, 108(1), 67-77.
[http://dx.doi.org/10.1016/0041-008X(91)90269-K] [PMID: 2006506]

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