Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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

Exploring the Molecular Mechanisms of 17β-HSD5-induced Carcinogenicity of Catha edulis via Molecular Modeling Approach

Author(s): Maria Saeed, Sajda Ashraf, Rashad Alsanosi, Hassan A. Alhazmi, Mohammed AlBratty, Asim Najmi, Asaad Khalid* and Zaheer Ul-Haq*

Volume 17, Issue 4, 2021

Published on: 05 October, 2020

Page: [418 - 428] Pages: 11

DOI: 10.2174/1573406416666201005142522

Price: $65

Abstract

Background: The tradition of khat chewing has been deep-rooted in the African and Arabian Peninsula for centuries. Due to its amphetamine-like psycho-stimulant or euphoric effect, khat has been used by millions in Somalia, Ethiopia, Saudi Arabia and Yemen. The long-term use of khat can induce many major health outcomes, which may be serious and irreversible.

Objective: Prolonged use of khat constituents has been associated with different types of cancers such as prostatic, breast and ovarian cancer. However, it has been very difficult to identify the molecular targets involved in khat carcinogenesis that interact with the Khat constituents by in vitro/in vivo experimental tools.

Methods: In silico tools were used to predict potential targets involved in the carcinogenesis of khat. Pass on-line prediction server was used for the prediction of a potential molecular target for khat constituents. Molecular Dynamics simulation and MM-GBSA calculation of the predicted target were carried out.

Results: Molecular Dynamics simulation and MM-GBSA calculation revealed that among khat constituents, β-sitosterol showed a high binding affinity towards 17β-HSD5. On the other hand, this study highlights for the first time some new interactions, which were observed in the case of cathine, cathinone and nerol during the simulation.

Conclusion: In silico molecular dynamic simulation tools were used for the first time to investigate the molecular mechanism of widely used leaves of psychoactive khat (Catha edulis) constituent. The present study provides deep insight to understand the effect of khat constituents involved in the impairment of the reproductive system and its binding to 17β-HSD5. ADMET profiling also suggested that few khat constituents do not fulfill the requirements of the Lipinski rule of five i.e. poor absorption and blood-brain barrier impermeability.

Keywords: Khat constituents, psychoactive substance, euphoria, 17β-HSD5, MD simulation, MM GB/PBSA, polycystic ovary syndrome.

« Previous
Graphical Abstract

[1]
Abdelwahab, S.I.; Alsanosy, R.M.; Rahim, B-E.; Mohan, S.; Taha, S.; Mohamed Elhassan, M.; El-Setouhy, M. Khat (Catha edulis Forsk.) dependence potential and pattern of use in Saudi Arabia. BioMed Res. Int., 2015, 2015604526
[http://dx.doi.org/10.1155/2015/604526] [PMID: 26380288]
[2]
Gebissa, E. Khat in the Horn of Africa: historical perspectives and current trends. J. Ethnopharmacol., 2010, 132(3), 607-614.
[http://dx.doi.org/10.1016/j.jep.2010.01.063] [PMID: 20227478]
[3]
Hansen, P. The ambiguity of khat in Somaliland. J. Ethnopharmacol., 2010, 132(3), 590-599.
[http://dx.doi.org/10.1016/j.jep.2010.02.028] [PMID: 20211235]
[4]
Lamina, S. Khat (Catha edulis): the herb with officio-legal, socio-cultural and economic uncertainty. S. Afr. J. Sci., 2010, 106(3-4), 1-4.
[http://dx.doi.org/10.4102/sajs.v106i3/4.155]
[5]
Colzato, L.S.; Ruiz, M.J.; van den Wildenberg, W.P.; Hommel, B. Khat use is associated with impaired working memory and cognitive flexibility. PLoS One, 2011, 6(6)e20602
[http://dx.doi.org/10.1371/journal.pone.0020602] [PMID: 21698275]
[6]
Engidawork, E. Pharmacological and toxicological effects of Catha edulis F.(Khat). Phytother. Res., 2017, 31(7), 1019-1028.
[http://dx.doi.org/10.1002/ptr.5832] [PMID: 28557133]
[7]
Nichols, T.; Khondkar, P.; Gibbons, S. The psychostimulant drug khat (Catha edulis): A mini-review. Phytochem. Lett., 2015, 13, 127-133.
[http://dx.doi.org/10.1016/j.phytol.2015.05.016]
[8]
Wabe, N.T.; Mohammed, M.A. What science says about khat (Catha edulis Forsk)? Overview of chemistry, toxicology and pharmacology. J. Exp. Integr. Med., 2012, 2(1), 29-37.
[http://dx.doi.org/10.5455/jeim.221211.rw.005]
[9]
Wabe, N.T. Chemistry, pharmacology, and toxicology of khat (catha edulis forsk): a review. Addict. Health, 2011, 3(3-4), 137-149.
[PMID: 24494129]
[10]
Toennes, S.W.; Harder, S.; Schramm, M.; Niess, C.; Kauert, G.F. Pharmacokinetics of cathinone, cathine and norephedrine after the chewing of khat leaves. Br. J. Clin. Pharmacol., 2003, 56(1), 125-130.
[http://dx.doi.org/10.1046/j.1365-2125.2003.01834.x PMID: 12848785]
[11]
Warfa, N.; Klein, A.; Bhui, K.; Leavey, G.; Craig, T.; Alfred Stansfeld, S. Khat use and mental illness: a critical review. Soc. Sci. Med., 2007, 65(2), 309-318.
[http://dx.doi.org/10.1016/j.socscimed.2007.04.038 PMID: 17544193]
[12]
Al-Motarreb, A.; Baker, K.; Broadley, K.J. Khat: pharmacological and medical aspects and its social use in Yemen. Phytother. Res., 2002, 16(5), 403-413.
[http://dx.doi.org/10.1002/ptr.1106] [PMID: 12203257]
[13]
Berihu, B.A.; Asfeha, G.G.; Welderufael, A.L.; Debeb, Y.G.; Zelelow, Y.B.; Beyene, H.A. Toxic effect of khat (Catha edulis) on memory: Systematic review and meta-analysis. J. Neurosci. Rural Pract., 2017, 8(01), 030-037.
[14]
Getasetegn, M. Chemical composition of Catha edulis (khat): a review. Phytochem. Rev., 2016, 15(5), 907-920.
[http://dx.doi.org/10.1007/s11101-015-9435-z]
[15]
Astatkie, A.; Demissie, M.; Berhane, Y.; Worku, A. Prevalence of and factors associated with regular khat chewing among university students in Ethiopia. Subst. Abuse Rehabil., 2015, 6, 41-50.
[http://dx.doi.org/10.2147/SAR.S78773] [PMID: 25750551]
[16]
Ayano, G.; Yohannis, K.; Abraha, M. Epidemiology of khat (Catha edulis) consumption among university students: a meta-analysis. BMC Public Health, 2019, 19(1), 150.
[http://dx.doi.org/10.1186/s12889-019-6495-9] [PMID: 30717743]
[17]
Chauhan, N.S.; Sharma, V.; Dixit, V.K.; Thakur, M. A review on plants used for improvement of sexual performance and virility. BioMed Res. Int., 2014, 2014868062
[http://dx.doi.org/10.1155/2014/868062] [PMID: 25215296]
[18]
Reda, A.A.; Moges, A.; Biadgilign, S.; Wondmagegn, B.Y. Prevalence and determinants of khat (Catha edulis) chewing among high school students in eastern Ethiopia: a cross-sectional study. PLoS One, 2012, 7(3)e33946
[http://dx.doi.org/10.1371/journal.pone.0033946] [PMID: 22479484]
[19]
Alele, P.E.; Ajayi, A.M.; Imanirampa, L. Chronic khat (Catha edulis) and alcohol marginally alter complete blood counts, clinical chemistry, and testosterone in male rats. J. Exp. Pharmacol., 2013, 2013(5), 33.
[http://dx.doi.org/10.2147/JEP.S46635] [PMID: 24348075]
[20]
Al-Shahrani, Z.; Al-Rawaji, A.; Al-Madouj, A.; Hayder, M.; Al-Zahrani, A.; Al-Mutlaq, H.; Bazarbashi, S. Cancer incidence report Saudi Arabia 2014; Saudi Cancer Registry, 2017, pp. 1-81.
[21]
Beckerleg, S. East African discourses on khat and sex. J. Ethnopharmacol., 2010, 132(3), 600-606.
[http://dx.doi.org/10.1016/j.jep.2010.08.057] [PMID: 20832464]
[22]
Byrns, M.C.; Penning, T.M. Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3): role in breast cancer and inhibition by non-steroidal anti-inflammatory drug analogs. Chem. Biol. Interact., 2009, 178(1-3), 221-227.
[http://dx.doi.org/10.1016/j.cbi.2008.10.024] [PMID: 19010312]
[23]
Carvalho, F. The toxicological potential of khat. J. Ethnopharmacol., 2003, 87(1), 1-2.
[http://dx.doi.org/10.1016/S0378-8741(03)00100-4] [PMID: 12787946]
[24]
Dimba, E.A.; Gjertsen, B.T.; Bredholt, T.; Fossan, K.O.; Costea, D.E.; Francis, G.W.; Johannessen, A.C.; Vintermyr, O.K. Khat (Catha edulis)-induced apoptosis is inhibited by antagonists of caspase-1 and -8 in human leukaemia cells. Br. J. Cancer, 2004, 91(9), 1726-1734.
[http://dx.doi.org/10.1038/sj.bjc.6602197] [PMID: 15477863]
[25]
Kebede, D.; Alem, A.; Mitike, G.; Enquselassie, F.; Berhane, F.; Abebe, Y.; Ayele, R.; Lemma, W.; Assefa, T.; Gebremichael, T. Khat and alcohol use and risky sex behaviour among in-school and out-of-school youth in Ethiopia. BMC Public Health, 2005, 5(1), 109.
[http://dx.doi.org/10.1186/1471-2458-5-109] [PMID: 16225665]
[26]
Xu, D.; Aka, J.A.; Wang, R.; Lin, S-X. 17beta-hydroxysteroid dehydrogenase type 5 is negatively correlated to apoptosis inhibitor GRP78 and tumor-secreted protein PGK1, and modulates breast cancer cell viability and proliferation. J. Steroid Biochem. Mol. Biol., 2017, 171, 270-280.
[http://dx.doi.org/10.1016/j.jsbmb.2017.04.009] [PMID: 28457968]
[27]
Hassan, N.A.; Gunaid, A.A.; Murray-Lyon, I.M. Khat (Catha edulis): health aspects of khat chewing. East. Mediterr. Health J., 2007, 13(3), 706-718.
[PMID: 17687845]
[28]
Odenwald, M.; Klein, A.; Warfa, N. Introduction to the special issue: the changing use and misuse of khat (Catha edulis)--tradition, trade and tragedy. J. Ethnopharmacol., 2010, 132(3), 537-539.
[http://dx.doi.org/10.1016/j.jep.2010.11.012] [PMID: 21115151]
[29]
Filimonov, D.; Lagunin, A.; Gloriozova, T.; Rudik, A.; Druzhilovskii, D.; Pogodin, P.; Poroikov, V. Prediction of the biological activity spectra of organic compounds using the PASS online web resource. Chem. Heterocycl. Compd., 2014, 50(3), 444-457.
[http://dx.doi.org/10.1007/s10593-014-1496-1]
[30]
Mohler, M.L.; Narayanan, R.; He, Y.; Miller, D.D.; Dalton, J.T. Hydroxysteroid dehydrogenase (17β-HSD3, 17β-HSD5, and 3α-HSD3) inhibitors: Extragonadal regulation of intracellular sex steroid hormone levels. Recent Pat. Endocr. Metab. Immune Drug Discov., 2007, 1(2), 103-118.
[http://dx.doi.org/10.2174/187221407780831957]
[31]
Nakamura, Y.; Hornsby, P.J.; Casson, P.; Morimoto, R.; Satoh, F.; Xing, Y.; Kennedy, M.R.; Sasano, H.; Rainey, W.E. Type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) contributes to testosterone production in the adrenal reticularis. J. Clin. Endocrinol. Metab., 2009, 94(6), 2192-2198.
[http://dx.doi.org/10.1210/jc.2008-2374] [PMID: 19336506]
[32]
Marchais-Oberwinkler, S.; Henn, C.; Möller, G.; Klein, T.; Negri, M.; Oster, A.; Spadaro, A.; Werth, R.; Wetzel, M.; Xu, K.; Frotscher, M.; Hartmann, R.W.; Adamski, J. 17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: protein structures, functions, and recent progress in inhibitor development. J. Steroid Biochem. Mol. Biol., 2011, 125(1-2), 66-82.
[http://dx.doi.org/10.1016/j.jsbmb.2010.12.013] [PMID: 21193039]
[33]
Poirier, D. 17β-Hydroxysteroid dehydrogenase inhibitors: a patent review. Expert Opin. Ther. Pat., 2010, 20(9), 1123-1145.
[http://dx.doi.org/10.1517/13543776.2010.505604] [PMID: 20645882]
[34]
Qin, K.; Ehrmann, D.A.; Cox, N.; Refetoff, S.; Rosenfield, R.L. Identification of a functional polymorphism of the human type 5 17β-hydroxysteroid dehydrogenase gene associated with polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 2006, 91(1), 270-276.
[http://dx.doi.org/10.1210/jc.2005-2012] [PMID: 16263811]
[35]
Gashawa, A.; Getachew, T. The chemistry of khat and adverse effect of khat chewing. Am. Sci. Res. J. Eng. Technol. Soc., 2014, 9(1), 35-46.
[36]
Szendrei, K. The chemistry of khat. Bull. Narc., 1980, 32(3), 5-35.
[PMID: 6911031]
[37]
Molecular Operating Environment (MOE). Chemical Computing Group Inc; 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7. 2019.
[38]
Amano, Y.; Yamaguchi, T.; Niimi, T.; Sakashita, H. Structures of complexes of type 5 17β-hydroxysteroid dehydrogenase with structurally diverse inhibitors: insights into the conformational changes upon inhibitor binding. Acta Crystallogr. D Biol. Crystallogr., 2015, 71(Pt 4), 918-927.
[http://dx.doi.org/10.1107/S1399004715002175] [PMID: 25849402]
[39]
Case, D.A. Ben-Shalom, Brozell, I.Y.; Cerutti, S.R.D.S.; Cheatham, T.E.; Cruzeiro, V.W.D.; Darden, T.A.; Duke, R.E.; Giambasu, G.; Gilson, M.K.; Gohlke, H.; Goetz, A.W.; Harris, R.; Izadi, S.; Izmailov, S.A.; Kasavajhala, K.; Kovalenko, A.; Krasny, R.; Kurtzman, T.; Lee, T.S.; LeGrand, S.; Li, P.; Lin, C.; Liu, J.; Luchko, T.; Luo, R.; Man, V.; Merz, K.M.; Miao, Y.; Mikhailovskii, O.; Monard, G.; Nguyen, H.; Onufriev, A.; Pan, F.; Pantano, S.; Qi, R.; Roe, D.R.; Roitberg, A.; Sagui, C.; Schott-Verdugo, S.; Shen, J.; Simmerling, C.L.; Skrynnikov, N.R.; Smith, J.; Swails, J.; Walker, R.C.; Wang, J.; Wilson, L.; Wolf, R.M.; Wu, X.; Xiong, Y.; Xue, Y.; York, D.M.; Kollman, P.A. AMBER 16; University of California: San Francisco, 2016.
[40]
Miyamoto, S.; Kollman, P.A. Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models. J. Comput. Chem., 1992, 13(8), 952-962.
[http://dx.doi.org/10.1002/jcc.540130805]
[41]
Roe, D.R.; Cheatham, T.E. III PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput., 2013, 9(7), 3084-3095.
[http://dx.doi.org/10.1021/ct400341p] [PMID: 26583988]
[42]
Humphrey, W.; Dalke, A.; Schulten, K. VMD: visual molecular dynamics. J. Mol. Graph., 1996, 14(1), 33-38. 27-28
[http://dx.doi.org/10.1016/0263-7855(96)00018-5] [PMID: 8744570]
[43]
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]
[44]
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]

Rights & Permissions Print Cite
Article Metrics
10
1
© 2024 Bentham Science Publishers | Privacy Policy