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Current Topics in Medicinal Chemistry

Editor-in-Chief

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

Review Article

QSAR Studies of Nitric Oxide Synthase Inhibitors

Author(s): Ioanna-Chrysoula Tsopka and Dimitra Hadjipavlou-Litina*

Volume 23, Issue 29, 2023

Published on: 02 November, 2023

Page: [2723 - 2734] Pages: 12

DOI: 10.2174/0115680266251348231026045329

Price: $65

Abstract

Background: Nitric oxide is a free radical bioregulator controlling homeostasis, vasodilation, and inhibition of platelet aggregation, significantly implicated in the nervous and immune system functionality. In vivo it is produced by nitric oxide synthases (NOSs).

Objective: Overproduction of nitric oxide is linked to several inflammatory, immunological, and neurodegenerative diseases and for that, various compounds have been synthesized as inhibitors of NOSs. In this review, the QSAR analyses were summarized in a variety of compounds as potent inhibitors of NOSs, and the models derived through 1D, 2D and 3D QSAR analyses.

Conclusion: Ten groups of various NOS inhibitors and 17 1D, 2D, and 3D QSAR models and analyses were presented and discussed. A lack of hydrophobic terms was noticed in most of the cases. Chemical substituents were selected considering the increase either of the hydrophilicity and/or of hydrophobicity, bulkiness supported steric interactions, and point to potent inhibitors. CMR (Calculated Molar Refractivity) a steric variable, with a negative sign, underlines the critical effects participating on (in) an active site on the enzymes. Indicator variables imply the influence of specific structural moieties. Electronic parameters were found to be significant.

Graphical Abstract

[1]
Furchgott, R. F. Endothelium-derived relaxing factor: Discovery, early studies, and identifcation as nitric oxide (Nobel lecture). Angewandte Chemie, 1999, 38(13-14), 1870-1880.
[2]
Strijdom, H.; Chamane, N.; Lochner, A. Nitric oxide in the cardiovascular system: A simple molecule with complex actions. Cardiovasc. J. Afr., 2009, 20(5), 303-310.
[PMID: 19907806]
[3]
Bogdan, C. Nitric oxide and the immune response. Nat. Immunol., 2001, 2(10), 907-916.
[http://dx.doi.org/10.1038/ni1001-907] [PMID: 11577346]
[4]
Wong, V.W.C.; Lerner, E. Nitric oxide inhibition strategies. Future Sci. OA, 2015, 1(1), fso.15.35.
[http://dx.doi.org/10.4155/fso.15.35] [PMID: 26634146]
[5]
Follmann, M.; Griebenow, N.; Hahn, M.G.; Hartung, I.; Mais, F.J.; Mittendorf, J.; Schäfer, M.; Schirok, H.; Stasch, J.P.; Stoll, F.; Straub, A. The chemistry and biology of soluble guanylate cyclase stimulators and activators. Angew. Chem. Int. Ed., 2013, 52(36), 9442-9462.
[http://dx.doi.org/10.1002/anie.201302588] [PMID: 23963798]
[6]
Nagpal, L.; Haque, M.M.; Saha, A.; Mukherjee, N.; Ghosh, A.; Ranu, B.C.; Stuehr, D.J.; Panda, K. Mechanism of inducible nitric-oxide synthase dimerization inhibition by novel pyrimidine imidazoles. J. Biol. Chem., 2013, 288(27), 19685-19697.
[http://dx.doi.org/10.1074/jbc.M112.446542] [PMID: 23696643]
[7]
Yokom, A.L.; Morishima, Y.; Lau, M.; Su, M.; Glukhova, A.; Osawa, Y.; Southworth, D.R. Architecture of the nitric-oxide synthase holoenzyme reveals large conformational changes and a calmodulin-driven release of the FMN domain. J. Biol. Chem., 2014, 289(24), 16855-16865.
[http://dx.doi.org/10.1074/jbc.M114.564005] [PMID: 24737326]
[8]
Hobbs, A.J.; Higgs, A.; Moncada, S. Inhibition of nitric oxide synthase as a potential therapeutic target. Annu Rev harmacol Toxicol, 1999, 39, 191-220.
[http://dx.doi.org/10.1146/annurev.pharmtox.39.1.191]
[9]
Kerwin, J.F., Jr; Heller, M. The arginine-nitric oxide pathway: A target for new drugs. Med. Res. Rev., 1994, 14(1), 23-74.
[http://dx.doi.org/10.1002/med.2610140103] [PMID: 7508539]
[10]
Kerwin, J.F., Jr; Lancaster, J.R., Jr; Feldman, P.L. Nitric oxide: A new paradigm for second messengers. J. Med. Chem., 1995, 38(22), 4343-4362.
[http://dx.doi.org/10.1021/jm00022a001] [PMID: 7473563]
[11]
Moore, W.M.; Webber, R.K.; Jerome, G.M.; Tjoeng, F.S.; Misko, T.P.; Currie, M.G. L-N6-(1-iminoethyl)lysine: A selective inhibitor of inducible nitric oxide synthase. J. Med. Chem., 1994, 37(23), 3886-3888.
[http://dx.doi.org/10.1021/jm00049a007] [PMID: 7525961]
[12]
Griffith, O.W.; Gross, S.S. Inhibitors of nitric oxide synthases.Methods in Nitric oxide research; Feelisch, M.; Stamler, J.S., Eds.; John Wiley and Sons: New York, 1996, pp. 187-208.
[13]
Bredt, D.S.; Hwang, P.M.; Glatt, C.E.; Lowenstein, C.; Reed, R.R.; Snyder, S.H. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature, 1991, 351(6329), 714-718.
[http://dx.doi.org/10.1038/351714a0] [PMID: 1712077]
[14]
Hansen, D.W., Jr Aminospiropiperidine quinazoline derivatives as selective inhibitors of nitric oxide synthase. Expert Opin. Ther. Pat., 2000, 10(1), 125-129.
[http://dx.doi.org/10.1517/13543776.10.1.125]
[15]
Hämäläinen, M.; Lilja, R.; Kankaanranta, H.; Moilanen, E. Inhibition of iNOS expression and NO production by anti-inflammatory steroids. Pulm. Pharmacol. Ther., 2008, 21(2), 331-339.
[http://dx.doi.org/10.1016/j.pupt.2007.08.003] [PMID: 17913526]
[16]
Kwon, S.; Bae, H.; Jo, J.; Yoon, S. Comprehensive ensemble in QSAR prediction for drug discovery. BMC Bioinformatics, 2019, 20(1), 521-533.
[http://dx.doi.org/10.1186/s12859-019-3135-4] [PMID: 31655545]
[17]
Patel, H.M.; Noolvi, M.N.; Sharma, P.; Jaiswal, V.; Bansal, S.; Lohan, S.; Kumar, S.S.; Abbot, V.; Dhiman, S.; Bhardwaj, V. Quantitative structure–activity relationship (QSAR) studies as strategic approach in drug discovery. Med. Chem. Res., 2014, 23(12), 4991-5007.
[http://dx.doi.org/10.1007/s00044-014-1072-3]
[18]
Pratim Roy, P.; Paul, S.; Mitra, I.; Roy, K. On two novel parameters for validation of predictive QSAR models. Molecules, 2009, 14(5), 1660-1701.
[http://dx.doi.org/10.3390/molecules14051660] [PMID: 19471190]
[19]
Kontogiorgis, C.A.; Hadjipavlou-Litina, D. Current trends in QSAR on NO donors and inhibitors of nitric oxide synthase (NOS). Med. Res. Rev., 2002, 22(4), 385-418.
[http://dx.doi.org/10.1002/med.10012] [PMID: 12111751]
[20]
BioByte Corp and C-QSAR program; Claremont, CA, 2002.
[21]
Hansch, C.; Kurup, A.; Garg, R.; Gao, H. Chem-bioinformatics and QSAR: A review of QSAR lacking positive hydrophobic terms. Chem. Rev., 2001, 101(3), 619-672.
[http://dx.doi.org/10.1021/cr0000067] [PMID: 11712499]
[22]
Hansch, C.; Klein, T.E. Molecular graphics and QSAR in the study of enzyme-ligand interactions. On the definition of bioreceptors. Acc. Chem. Res., 1986, 19(12), 392-400.
[http://dx.doi.org/10.1021/ar00132a003]
[23]
Crane, B.R.; Arvai, A.S.; Ghosh, D.K.; Wu, C.; Getzoff, E.D.; Stuehr, D.J.; Tainer, J.A. Structure of nitric oxide synthase oxygenase dimer with pterin and substrate. Science, 1998, 279(5359), 2121-2126.
[http://dx.doi.org/10.1126/science.279.5359.2121] [PMID: 9516116]
[24]
Kumar, V.; Gupta, S.P.A. A QSAR and molecular modeling study on a series of 3, 4-dihydro-1-isoquinolinamines and thienopyridines acting as nitric oxide synthase inhibitors. Indian J. Biochem. Biophys., 2013, 50(1), 72-79.
[PMID: 23617077]
[25]
Bharti, V.D.; Gupta, S.P.; Kumar, H. A quantitative structure-activity relationship (QSAR) study on a few series of potent, highly selective inhibitors of nitric oxide synthase. Indian J. Biochem. Biophys., 2014, 51(1), 29-36.
[26]
Unger, S.H. Molecular Connectivity in Structure–activity Analysis. J. Pharm. Sci., 1987, 76(3), 269-270.
[http://dx.doi.org/10.1002/jps.2600760325]
[27]
Kier, L.B.; Hall, L.H. Derivation and significance of valence molecular connectivity. J. Pharm. Sci., 1981, 70(6), 583-589.
[http://dx.doi.org/10.1002/jps.2600700602] [PMID: 7252795]
[28]
Kumar, H.; Siddiqui, A.; Gupta, S. A quantitative structure-activity relationship study on some imidazoles and 2-aminopyridines acting as nitric oxide synthase (NOS) inhibitors. Lett. Drug Des. Discov., 2013, 10(7), 666-674.
[http://dx.doi.org/10.2174/1570180811310070015]
[29]
Halder, A.K.; Mukherjee, A.; Adhikari, N.; Saha, A.; Jha, T. Nitric oxide synthase (NOS) inhibitors in cancer angiogenesis. Curr. Enzym. Inhib., 2016, 12, 49-66.
[http://dx.doi.org/10.2174/1573408012666151126185456]
[30]
Tanaka, I. Nanoinformatics; Springer: Singapore, 2018.
[http://dx.doi.org/10.1007/978-981-10-7617-6]
[31]
Sawada, R.; Kotera, M.; Yamanishi, Y. Benchmarking a wide range of chemical descriptors for drug-target interaction prediction using a chemogenomic approach. Mol. Inform., 2014, 33(11-12), 719-731.
[http://dx.doi.org/10.1002/minf.201400066] [PMID: 27485418]
[32]
Handbook of Chemoinformatics Algorithms; Chapman and Hall, 2010.
[http://dx.doi.org/10.1201/9781420082999]
[33]
Suaifan, G.; Shehadeh, M.; Al-Ijel, H.; Al-Jamal, K.T.; Taha, M. Pharmacophore and QSAR modeling of neuronal nitric oxide synthase ligands and subsequent validation and in silico search for new scaffolds. Med. Chem., 2016, 12(4), 371-393.
[http://dx.doi.org/10.2174/1573406411666151002130609] [PMID: 26427928]
[34]
Evans, D.A.; Doman, T.N.; Thorner, D.A.; Bodkin, M.J. 3D QSAR methods: Phase and Catalyst compared. J. Chem. Inf. Model., 2007, 47(3), 1248-1257.
[http://dx.doi.org/10.1021/ci7000082] [PMID: 17477520]
[35]
Mohd Faudzi, S.M.; Leong, S.W.; Abas, F.; Mohd Aluwi, M.F.F.; Rullah, K.; Lam, K.W.; Ahmad, S.; Tham, C.L.; Shaari, K.; Lajis, N.H. Synthesis, biological evaluation and QSAR studies of diarylpentanoid analogues as potential nitric oxideinhibitors. MedChemComm, 2015, 6(6), 1069-1080.
[http://dx.doi.org/10.1039/C4MD00541D]
[36]
Zhang, H.; Zan, J.; Yu, G.; Jiang, M.; Liu, P. A combination of 3D-QSAR, molecular docking and molecular dynamics simulation studies of benzimidazole-quinolinone derivatives as iNOS inhibitors. Int. J. Mol. Sci., 2012, 13(9), 11210-11227.
[http://dx.doi.org/10.3390/ijms130911210] [PMID: 23109848]
[37]
Mittal, A.; Arora, R.; Kakkar, R. Pharmacophore modeling, 3D-QSAR and molecular docking studies of quinazolines and aminopyridines as selective inhibitors of inducible nitric oxide synthase. J. Theor. Comput. Chem., 2019, 18(1), 1950002-1950008.
[http://dx.doi.org/10.1142/S0219633619500020]
[38]
Hu, X.L.; Lv, X.Y.; Wang, R.; Long, H.; Feng, J.H.; Wang, B.L.; Shen, W.; Liu, H.; Xiong, F.; Zhang, X.Q.; Ye, W.C.; Wang, H. Optimization of N -phenylpropenoyl- L -amino acids as potent and selective inducible nitric oxide synthase inhibitors for parkinson’s disease. J. Med. Chem., 2021, 64(11), 7760-7777.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00578] [PMID: 34019417]

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