Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Leveraging on Active Site Similarities; Identification of Potential Inhibitors of Zinc-Finger and UFSP domain Protein (ZUFSP)

Author(s): Mary B. Ajadi, Opeyemi S. Soremekun, Adeniyi T. Adewumi, Hezekiel M. Kumalo and Mahmoud E.S. Soliman*

Volume 22, Issue 7, 2021

Published on: 30 July, 2020

Page: [995 - 1004] Pages: 10

DOI: 10.2174/1389201021666200730151218

Price: $65

Abstract

Background: ZUFSP (Zinc-finger and UFSP domain protein) is a novel representative member of the recently characterized seventh class of deubiquitinating enzymes (DUBs). Due to the roles DUBs play in genetic instability, they have become a major drug target in cancer and neurodegenerative diseases. ZUFSP, being a DUB enzyme has also been implicated in genetic stability. However, no lead compound has been developed to target ZUFSP.

Objective/Methods: Therefore, in this study, we used a combined drug repurposing, virtual screening and per-Residue Energy Decomposition (PRED) to identify ZUFSP inhibitors with therapeutic potential. 3-bromo-6-{[4-hydroxy-1-3(3-phenylbutanoyl)piperidin-4-yl]methyl}-4H,5H,6H,7H-thieno[2,3- C]pyridine-7-one (BHPTP) which is an inhibitor of USP7 was repurposed to target ZUFSP. The rationale behind this is based on the similarity of the active between USP7 and ZUFSP.

Results: PRED of the binding between BHPTP and ZUFSP revealed Cys223, Arg408, Met410, Asn460, and Tyr465 as the crucial residues responsible for this interaction. The pharmacophoric moieties of BHPTP responsible for this binding along with other physiochemical properties were used as a filter to retrieve potential ligands. 799 compounds were retrieved, ZINC083241427, ZINC063648749, and ZINC063648753 were selected due to the binding energy they exhibited. Cheminformatics analysis revealed that the compounds possess high membrane permeability, however, BHPTP had a low membrane permeability. Furthermore, the compounds are drug like, having obeyed Lipinski’s rule of five.

Conclusion: Taken together, findings from this study put ZINC083241427, ZINC063648749, and ZINC063648753 as potential ZUFSP inhibitor, however, more experimental validation is required to unravel the mechanism of actions of these compounds.

Keywords: ZUFSP, drug repurposing, pharmacophore modeling, per-residue energy decomposition, genomic instability, cancer.

« Previous Next »
Graphical Abstract

[1]
Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin., 2011, 61(2), 69-90.
[http://dx.doi.org/10.3322/caac.20107] [PMID: 21296855]
[2]
Singh, E.; Underwood, J.M.; Nattey, C.; Babb, C.; Sengayi, M.; Kellett, P. South African National Cancer Registry: Effect of withheld data from private health systems on cancer incidence estimates. S. Afr. Med. J., 2015, 105(2), 107-109.
[http://dx.doi.org/10.7196/SAMJ.8858] [PMID: 26242527]
[3]
Dagenais, G.R.; Leong, D.P.; Rangarajan, S.; Lanas, F.; Lopez-Jaramillo, P.; Gupta, R.; Diaz, R.; Avezum, A.; Oliveira, G.B.F.; Wielgosz, A.; Parambath, S.R.; Mony, P.; Alhabib, K.F.; Temizhan, A.; Ismail, N.; Chifamba, J.; Yeates, K.; Khatib, R.; Rahman, O.; Zatonska, K.; Kazmi, K.; Wei, L.; Zhu, J.; Rosengren, A.; Vijayakumar, K.; Kaur, M.; Mohan, V.; Yusufali, A.H.; Kelishadi, R.; Teo, K.K.; Joseph, P.; Yusuf, S. Variations in common diseases, hospital admissions, and deaths in middle-aged adults in 21 countries from five continents (PURE): A prospective cohort study. Lancet, 2020, 395(10226), 785-794.
[http://dx.doi.org/10.1016/S0140-]
[4]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics. Cancer J. Clin., 2020, 70(1), 7-30.
[http://dx.doi.org/10.3322/caac.21590]]
[5]
Grönberg, H. Prostate cancer epidemiology. Lancet, 2003, 361(9360), 859-864.
[http://dx.doi.org/10.1016/S0140-6736(03)12713-4] [PMID: 12642065]
[6]
Huang, X.; Dixit, V.M. Drugging the undruggables: Exploring the ubiquitin system for drug development. Cell Res., 2016, 26(4), 484-498.
[http://dx.doi.org/10.1038/cr.2016.31] [PMID: 27002218]
[7]
Zheng, Q.; Huang, T.; Zhang, L.; Zhou, Y.; Luo, H.; Xu, H.; Wang, X. Dysregulation of ubiquitin-proteasome system in neurodegenerative diseases. Front. Aging Neurosci., 2016, 8, 303.
[http://dx.doi.org/10.3389/fnagi.2016.00303] [PMID: 28018215]
[8]
Siegel, R.L.; Miller, K.D.; Fedewa, S.A.; Ahnen, D.J.; Meester, R.G.S.; Barzi, A.; Jemal, A. Colorectal cancer statistics. Cancer J. Clin., 2017, 67(3), 177-193.
[http://dx.doi.org/10.3322/caac.21395]
[9]
Zhang, W.; Sidhu, S.S. Development of inhibitors in the ubiquitination cascade. FEBS Lett., 2014, 588(2), 356-367.
[http://dx.doi.org/10.1016/j.febslet.2013.11.003] [PMID: 24239534]
[10]
Heideker, J.; Wertz, I.E. DUBs, the regulation of cell identity and disease. Biochem. J., 2015, 465(1), 1-26.
[http://dx.doi.org/10.1042/BJ20140496] [PMID: 25631680]
[11]
Glickman, M.H.; Ciechanover, A. The ubiquitin-proteasome proteolytic pathway: Destruction for the sake of construction. Physiological reviews; Amer. Physiol. Soc., 2002, pp. 373-428.
[http://dx.doi.org/10.1152/physrev.00027.2001]
[12]
Emmanuel, I.A.; Olotu, F.; Agoni, C.; Soliman, M.E.S. Broadening the horizon: Integrative pharmacophore-based and cheminformatics screening of novel chemical modulators of mitochondria ATP synthase towards interventive Alzheimer’s disease therapy. Med. Hypotheses, 2019, 130, 109277.
[http://dx.doi.org/10.1016/j.mehy.2019.109277] [PMID: 31383337]
[13]
Soremekun, O.S.; Olotu, F.A.; Agoni, C.; Soliman, M.E.S. Drug promiscuity: Exploring the polypharmacology potential of 1, 3, 6-trisubstituted 1, 4-diazepane-7-ones as an inhibitor of the ‘god father’ of immune checkpoint. Comput. Biol. Chem., 2019, 80, 433-440.
[http://dx.doi.org/10.1016/j.compbiolchem.2019.05.009] [PMID: 31146119]
[14]
Lecker, S.H.; Goldberg, A.L.; Mitch, W.E. Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J. Amer. Soc. Nephrol., 2006, 1807-1819.
[http://dx.doi.org/10.1681/ASN.2006010083]
[15]
Nasab, R.R.; Hassanzadeh, F.; Khodarahmi, G.A.; Rostami, M.; Mirzaei, M.; Jahanian-Najafabadi, A.; Mansourian, M. Docking study, synthesis and antimicrobial evaluation of some novel 4-anilinoquinazoline derivatives. Res. Pharm. Sci., 2017, 12(5), 425-433.
[http://dx.doi.org/10.4103/1735-5362.213988] [PMID: 28974981]
[16]
Pickart, C.M. Back to the future with ubiquitin. Cell, 2004, 23, 181-190.
[http://dx.doi.org/10.1016/S0092-8674(03)01074-2]
[17]
Kulathu, Y.; Komander, D. Atypical ubiquitylation-the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat. Rev. Mol. Cell Biol., 2012, 13(8), 508-523.
[http://dx.doi.org/10.1038/nrm3394]
[18]
Sanner, M.F. Python: A programming language for software integration and development. J. Mol. Graph. Model., 1999, 17(1), 57-61.
[PMID: 10660911]
[19]
Amerik, A.Y.; Hochstrasser, M. Mechanism and function of deubiquitinating enzymes. Biochim. et Biophys. Acta – Mol. Cell Res., 2004, 1695, 189-207.
[http://dx.doi.org/10.1016/j.bbamcr.2004.10.003]
[20]
Kwasna, D.; Abdul Rehman, S.A.; Natarajan, J.; Matthews, S.; Madden, R.; De Cesare, V.; Weidlich, S.; Virdee, S.; Ahel, I.; Gibbs-Seymour, I.; Kulathu, Y. Discovery and characterization of ZUFSP/ZUP1, a distinct deubiquitinase class important for genome stability. Mol. Cell, 2018, 70(1), 150-164.e6.
[http://dx.doi.org/10.1016/j.molcel.2018.02.023] [PMID: 29576527]
[21]
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]
[22]
Maurer, P.; Laio, A.; Hugosson, H.W.; Colombo, M.C.; Rothlisberger, U. Automated parametrization of biomolecular force fields from Quantum Mechanics/Molecular Mechanics (QM/MM) simulations through force matching. J. Chem. Theory Comput., 2007, 3(2), 628-639.
[http://dx.doi.org/10.1021/ct600284f] [PMID: 26637041]
[23]
Olotu, F.A.; Soliman, M.E.S. The design of potent reactivators in cancer therapy. Dynamic perspectives into the mechanisms of mutation-induced p53-DNA binding loss and inactivation using active perturbation theory: Structural and molecular insights toward the design of potent reactivators in cancer therapy. J. Cell. Biochem., 2019, 120(1), 951-966.
[http://dx.doi.org/10.1002/jcb.27458] [PMID: 30160791]
[24]
Hanpude, P.; Bhattacharya, S.; Dey, A.K.; Maiti, T.K. Deubiquitinating enzymes in cellular signaling and disease regulation. IUBMB Life, 2015, 67(7), 544-555.
[http://dx.doi.org/10.1002/iub.1402]
[25]
Dominguez, C.; Boelens, R.; Bonvin, A.M.J.J. Haddock: A protein-protein docking approach based on biochemical or biophysical information. J. Am. Chem. Soc., 2003, 125(7), 1731-1737.
[http://dx.doi.org/10.1021/ja026939x] [PMID: 12580598]
[26]
Kollman, P.A.; Massova, I.; Reyes, C.; Kuhn, B.; Huo, S.; Chong, L.; Lee, M.; Lee, T.; Duan, Y.; Wang, W.; Donini, O.; Cieplak, P.; Srinivasan, J.; Case, D.A.; Cheatham, T.E., III Calculating structures and free energies of complex molecules: Combining molecular mechanics and continuum models. Acc. Chem. Res., 2000, 33(12), 889-897.
[http://dx.doi.org/10.1021/ar000033j] [PMID: 11123888]
[27]
Halgren, T.A. Identifying and characterizing binding sites and assessing druggability. J. Chem. Inf. Model., 2009, 49(2), 377-389.
[http://dx.doi.org/10.1021/ci800324m] [PMID: 19434839]
[28]
Shoichet, B.K. Virtual screening of chemical libraries. Nature, 2004, 432, 862-865.
[http://dx.doi.org/10.1038/nature03197]
[29]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[30]
Morin, D.; Elimadi, A.; Sapena, R.; Crevat, A.; Carrupt, P.A.; Testa, B.; Tillement, J.P. Evidence for the existence of [3H]-trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore. Br. J. Pharmacol., 1998, 123(7), 1385-1394.
[http://dx.doi.org/10.1038/sj.bjp.0701755] [PMID: 9579734]
[31]
Muheem, A.; Shakeel, F.; Jahangir, M.A.; Anwar, M.; Mallick, N.; Jain, G.K.; Warsi, M.H.; Ahmad, F.J. A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives. Saudi Pharm. J., 2016, 24(4), 413-428.
[http://dx.doi.org/10.1016/j.jsps.2014.06.004] [PMID: 27330372]
[32]
Genheden, S.; Ryde, U. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin. Drug Discov., 2015, 10(5), 449-461.
[http://dx.doi.org/10.1517/17460441.2015.1032936] [PMID: 25835573]
[33]
Krieger, E.; Nabuurs, S.B.; Vriend, G. Chapter 25: Homology modeling.Struct. Bioinformatics; , 2003, 44, pp. 507-521.
[http://dx.doi.org/10.1007/978-1-61779-588-6]
[34]
Martínez, L. Automatic identification of mobile and rigid substructures in molecular dynamics simulations and fractional structural fluctuation analysis. PLoS One, 2015, 10(3), e0119264.
[http://dx.doi.org/10.1371/journal.pone.0119264] [PMID: 25816325]
[35]
Soremekun, O.S.; Olotu, F.A.; Agoni, C.; Soliman, M.E.S. Recruiting monomer for dimer formation: Resolving the antagonistic mechanisms of novel immune check point inhibitors against Programmed Death Ligand-1 in cancer immunotherapy. Mol. Simul., 2019, 45(10), 777-789.
[http://dx.doi.org/10.1080/08927022.2019.1593977]
[36]
Malvezzi, M.; Bertuccio, P.; Rosso, T.; Rota, M.; Levi, F.; La Vecchia, C.; Negri, E. European cancer mortality predictions for the year 2015: Does lung cancer have the highest death rate in EU women? Ann. Oncol., 2015, 26(4), 779-786.
[http://dx.doi.org/10.1093/annonc/mdv001] [PMID: 25623049]
[37]
Bornot, A.; Etchebest, C.; De Brevern, A.G. Predicting protein flexibility through the prediction of local structures. Proteins, 2011, 79(3), 839-852.
[http://dx.doi.org/10.1002/prot.22922]
[38]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[39]
Machaba, K.E.; Mhlongo, N.N.; Soliman, M.E.S. Induced mutation proves a potential target for TB therapy: A molecular dynamics study on LprG. Cell Biochem. Biophys., 2018, 76(3), 345-356.
[http://dx.doi.org/10.1007/s12013-018-0852-7] [PMID: 30073572]
[40]
Spassov, V.Z.; Yan, L.; Flook, P.K. The dominant role of side-chain backbone interactions in structural realization of amino acid code. ChiRotor: A side-chain prediction algorithm based on side-chain backbone interactions. Protein Sci., 2007, 16(3), 494-506.
[http://dx.doi.org/10.1110/ps.062447107] [PMID: 17242380]
[41]
Chaffey, N.; Alberts, B.; Johnson, A.; Lewis, J.; Raff, M.; Roberts, K.; Walter, P. Molecular biology of the cell.4th edn. Ann. Bot; , 2003, 91, p. (3)401.
[http://dx.doi.org/10.1093/aob/mcg02]
[42]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2012, 4-17.
[http://dx.doi.org/10.1016/j.addr.2012.09.019]
[43]
Bhakat, S.; Martin, A.J.M.; Soliman, M.E.S. An integrated molecular dynamics, principal component analysis and residue interaction network approach reveals the impact of M184V mutation on HIV reverse transcriptase resistance to lamivudine. Mol. Biosyst., 2014, 10(8), 2215-2228.
[http://dx.doi.org/10.1039/C4MB00253A] [PMID: 24931725]
[44]
Trott, O.; Olson, A.J. Software news and update AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, Efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[http://dx.doi.org/10.1002/jcc.21334] [PMID: 19499576]
[45]
Kumalo, H.M.; Soliman, M.E. Per-residue energy footprints-based pharmacophore modeling as an enhanced in silico approach in drug discovery: A case study on the identification of novel β-secretase1 (BACE1) inhibitors as anti-alzheimer agents. Cell. Mol. Bioeng., 2016, 9, 175-189.
[http://dx.doi.org/10.1007/s12195-015-0421-8]
[46]
Ndagi, U.; Mhlongo, N.N.; Soliman, M.E. The impact of Thr91 mutation on c-Src resistance to UM-164: Molecular dynamics study revealed a new opportunity for drug design. Mol. Biosyst., 2017, 13(6), 1157-1171.
[http://dx.doi.org/10.1039/C6MB00848H] [PMID: 28463369]
[47]
Pitera, J.W. Expected distributions of root-mean-square positional deviations in proteins. J. Phys. Chem. B, 2014, 118(24), 6526-6530.
[http://dx.doi.org/10.1021/jp412776d] [PMID: 24655018]
[48]
Koes, D.R.; Camacho, C.J. ZINC Pharmer: Pharmacophore search of the zinc database. Nucleic Acids Res., 2012, 40, W409-W414.
[http://dx.doi.org/10.1093/nar/gks378]
[49]
Ncube, N.B.; Ramharack, P.; Soliman, M.E.S. An “all-in-one” pharmacophoric architecture for the discovery of potential broad-spectrum anti-flavivirus drugs. Appl. Biochem. Biotechnol., 2018, 185, 799-814.
[http://dx.doi.org/10.1007/s12010-017-2690-2]

Rights & Permissions Print Cite
Article Metrics
12
1
© 2024 Bentham Science Publishers | Privacy Policy