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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Inhibition Profiling of Urease and Carbonic Anhydrase II by High- Throughput Screening and Molecular Docking Studies of Structurally Diverse Organic Compounds

Author(s): Majid Ali, Syed Majid Bukhari*, Asma Zaidi, Farhan A. Khan, Umer Rashid, Neelum Tahir, Baseerat Rabbani and Umar Farooq

Volume 18, Issue 3, 2021

Published on: 05 October, 2020

Page: [299 - 312] Pages: 14

DOI: 10.2174/1570180817999201005200505

Price: $65

Abstract

Background: Structurally diverse organic compounds and available drugs were screened against urease and carbonic anhydrase II in a formulation acceptable for high-throughput screening.

Objective: The study was conducted to find out potential inhibitors of urease and carbonic anhydrase II.

Methods: Quantification of the possible HITs was carried out by determining their IC50 values.

Results: The results of several screened compounds, including derivatives of oxadiazole, coumarins, chromane-2, 4-diones and metal complexes of cysteine-omeprazole showed promising inhibitory activities with IC50 ranging from 47 μM to 412 μM against the urease. The interactions of active compounds with active sites of enzymes were investigated through molecular docking studies which revealed that (R)-1-(4-amino-4-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl) butyl) guanidine possessing IC50 of 47 μM interacts with one of the nickel metal atoms of urease besides further interactions as predictable hydrogen bonds with KCX490, Asp633, His492, His407 and His409 along with Ala440 and 636. Bi-ligand metal complexes of 4-aminoantipyrine based Schiff bases showed activation of urease with AC50 ranging from 68 μM to 112 μM. Almost 21 compounds with varying functional groups including pyrimidines, oxadiazoles, imidazoles, hydrazides and tin based compounds were active carbonic anhydrase II inhibitors presenting 98 μM to 390 μM IC50 values. Several N-substituted sulfonamide derivatives were inactive against carbonic anhydrase II.

Conclusion: Among all the screened compounds, the highly active inhibitor of carbonic anhydrase II was (4-(3-hydroxyphenyl)-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl) methanone with IC50 of 98.0 μM. This particular compound showed metallic interaction with Zn ion of carbonic anhydrase II through the hydroxyl group of the phenyl ring.

Keywords: Urease, carbonic anhydrase II, molecular docking studies, enzyme inhibition, IC50, organic compounds.

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[1]
Dixon, N.E.; Gazzola, C.; Watters, J.J.; Blakely, R.L.; Zerner, B. Inhibition of Jack Bean urease (EC 3.5.1.5) by acetohydroxamic acid and by phosphoramidate. An equivalent weight for urease. J. Am. Chem. Soc., 1975, 97(14), 4130-4131.
[http://dx.doi.org/10.1021/ja00847a044] [PMID: 1159215]
[2]
Mobley, H.L.; Hausinger, R.P. Microbial ureases: Significance, regulation, and molecular characterization. Microbiol. Rev., 1989, 53(1), 85-108.
[http://dx.doi.org/10.1128/MMBR.53.1.85-108.1989] [PMID: 2651866]
[3]
Vassiliou, S.; Grabowiecka, A.; Kosikowska, P.; Yiotakis, A.; Kafarski, P.; Berlicki, Ł. Design, synthesis, and evaluation of novel organophosphorus inhibitors of bacterial ureases. J. Med. Chem., 2008, 51(18), 5736-5744.
[http://dx.doi.org/10.1021/jm800570q] [PMID: 18717581]
[4]
Montecucco, C.; Rappuoli, R. Living dangerously: How Helicobacter pylori survives in the human stomach. Nat. Rev. Mol. Cell Biol., 2001, 2(6), 457-466.
[http://dx.doi.org/10.1038/35073084] [PMID: 11389469]
[5]
Abbas, N.; Khan, I.; Batool, S.; Ali, M.; Farooq, U.; Khan, A.; Hameed, S.; White, J.M.; Ibrar, A. 2-Nitrobenzohydrazide as a potent urease inhibitor: Synthesis, characterization and single crystal X-ray diffraction analysis. J. Chem. Soc. Pak., 2018, 40, 165-170.
[6]
Uesato, S.; Hashimoto, Y.; Nishino, M.; Nagaoka, Y.; Kuwajima, H. N-substituted hydroxyureas as urease inhibitors. Chem. Pharm. Bull. (Tokyo), 2002, 50(9), 1280-1282.
[http://dx.doi.org/10.1248/cpb.50.1280] [PMID: 12237554]
[7]
Odake, S.; Morikawa, T.; Tsuchiya, M.; Imamura, L.; Kobashi, K. Inhibition of Helicobacter pylori urease activity by hydroxamic acid derivatives. Biol. Pharm. Bull., 1994, 17(10), 1329-1332.
[http://dx.doi.org/10.1248/bpb.17.1329] [PMID: 7874052]
[8]
Zhou, J.T.; Li, C.L.; Tan, L.H.; Xu, Y.F.; Liu, Y.H.; Mo, Z.Z.; Dou, Y.X.; Su, R.; Su, Z.R.; Huang, P.; Xie, J.H. Inhibition of Helicobacter pylori and its associated urease by palmatine: Investigation on the potential mechanism. PLoS One, 2017, 12(1), e0168944.
[http://dx.doi.org/10.1371/journal.pone.0168944] [PMID: 28045966]
[9]
Abid, O.U.; Babar, T.M.; Ali, F.I.; Ahmed, S.; Wadood, A.; Rama, N.H.; Uddin, R. Zaheer-Ul-Haq; Khan, A.; Choudhary, M.I. Identification of novel urease inhibitors by high-throughput virtual and in vitro screening. ACS Med. Chem. Lett., 2010, 1(4), 145-149.
[http://dx.doi.org/10.1021/ml100068u] [PMID: 24900188]
[10]
McKenna, R.; Frost, S., Eds.; Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications; Springer Netherlands, 2014.
[11]
Supuran, C.T. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat. Rev. Drug Discov., 2008, 7(2), 168-181.
[http://dx.doi.org/10.1038/nrd2467] [PMID: 18167490]
[12]
Supuran, C.T. Structure-based drug discovery of carbonic anhydrase inhibitors. J. Enzyme Inhib. Med. Chem., 2012, 27(6), 759-772.
[http://dx.doi.org/10.3109/14756366.2012.672983] [PMID: 22468747]
[13]
Supuran, C.T. Advances in structure-based drug discovery of carbonic anhydrase inhibitors. Expert Opin. Drug Discov., 2017, 12(1), 61-88.
[http://dx.doi.org/10.1080/17460441.2017.1253677] [PMID: 27783541]
[14]
Supuran, C.T. How many carbonic anhydrase inhibition mechanisms exist? J. Enzyme Inhib. Med. Chem., 2016, 31(3), 345-360.
[http://dx.doi.org/10.3109/14756366.2015.1122001] [PMID: 26619898]
[15]
McKenna, R.; Supuran, C.T. Carbonic anhydrase inhibitors drug design.In: Carbonic anhydrase: mechanism, regulation, links to disease, and industrial applications; Springer: Dordrecht, 2014, pp. 291-323.
[http://dx.doi.org/10.1007/978-94-007-7359-2_15]
[16]
Supuran, C.T. Drug interaction considerations in the therapeutic use of carbonic anhydrase inhibitors. Expert Opin. Drug Metab. Toxicol., 2016, 12(4), 423-431.
[http://dx.doi.org/10.1517/17425255.2016.1154534] [PMID: 26878088]
[17]
Winum, J.Y.; Supuran, C.T. Recent advances in the discovery of zinc-binding motifs for the development of carbonic anhydrase inhibitors. J. Enzyme Inhib. Med. Chem., 2015, 30(2), 321-324.
[http://dx.doi.org/10.3109/14756366.2014.913587] [PMID: 24939097]
[18]
Weatherburn, M.W. Phenol-hypochlorite reaction for determination of ammonia. Anal. Chem., 1967, 39, 971-974.
[http://dx.doi.org/10.1021/ac60252a045]
[19]
Shank, R.P.; Doose, D.R.; Streeter, A.J.; Bialer, M. Plasma and whole blood pharmacokinetics of Topiramate: The role of carbonic anhydrase. Epilepsy Res., 2005, 63(2-3), 103-112.
[http://dx.doi.org/10.1016/j.eplepsyres.2005.01.001] [PMID: 15715969]
[20]
Pocker, Y.; Stone, J.T. The catalytic versatility of erythrocyte carbonic anhydrase. 3. Kinetic studies of the enzyme-catalyzed hydrolysis of p-Nitrophenyl acetate. Biochemistry, 1967, 6(3), 668-678.
[http://dx.doi.org/10.1021/bi00855a005] [PMID: 4960944]
[21]
Rose, P.W.; Prlić, A.; Bi, C.; Bluhm, W.F.; Christie, C.H.; Dutta, S.; Green, R.K.; Goodsell, D.S.; Westbrook, J.D.; Woo, J.; Young, J.; Zardecki, C.; Berman, H.M.; Bourne, P.E.; Burley, S.K. The RCSB Protein Data Bank: Views of structural biology for basic and applied research and education. Nucleic Acids Res., 2015, 43(Database issue), D345-D356.
[http://dx.doi.org/10.1093/nar/gku1214] [PMID: 25428375]
[22]
Ibrar, A.; Khan, A.; Ali, M.; Sarwar, R.; Mehsud, S.; Farooq, U.; Halimi, S.M.A.; Khan, I.; Al-Harrasi, A. Combined in vitro and in silico studies for the anticholinesterase activity and pharmacokinetics of coumarinyl thiazoles and oxadiazoles. Front Chem., 2018, 6, 61.
[http://dx.doi.org/10.3389/fchem.2018.00061] [PMID: 29632858]
[23]
Mills, N. ChemDraw Ultra 10.0 CambridgeSoft, 100 CambridgePark Drive, Cambridge, MA 02140 www. cambridgesoft. com Commercial Price: 1910fordownload, 2150 for CD-ROM; Academic Price: 710fordownload, 800 for CD-ROM.
[24]
Hanif, M.; Shoaib, K.; Saleem, M.; Hasan Rama, N.; Zaib, S.; Iqbal, J. Synthesis, urease inhibition, antioxidant, antibacterial, and molecular docking studies of 1,3,4-oxadiazole derivatives. ISRN Pharmacol., 2012, 2012, 928901.
[http://dx.doi.org/10.5402/2012/928901] [PMID: 22934191]

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