Journal of the Serbian Chemical Society 2023 Volume 88, Issue 2, Pages: 123-139
https://doi.org/10.2298/JSC220912078B
Full text (
3960 KB)
Cited by
Screening the binding affinity of bile acid derivatives for the glucocorticoid receptor ligand-binding domain
Bjedov Srđan 
(Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia), srdjan.bjedov@dh.uns.ac.rs
Bekić Sofija (Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia)
Marinović Maja (Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia)
Škorić Dušan (Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia)
Pavlović Ksenija (Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia)
Ćelić Anđelka (Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia)
Petri Edward (Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia)
Sakač Marija (Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia)
The necessity of anti-inflammatory drugs such as glucocorticoids has been evident during the COVID-19 pandemic. Glucocorticoids, are the standard therapy for the treatment of moderate and severe COVID-19 patients. However, serious side effects limit the use of these drugs, and anti-inflammatory drugs with better pharmacological properties are urgently required. Bile acids are of interest, because of their anti-inflammatory and immunomodulatory properties, facilitated through an unclear mechanism involving transmembrane and nuclear receptors. In this work, we screened the binding activity of a number of bile acid derivatives, for the ligand-binding domain of glucocorticoid receptor (GR-LBD), the most important receptor for anti-inflammatory processes. Tested compounds include oximes, lactones, lactams, tetrazoles, dienones, C-24 alcohols and cholic acid amides. Cholic acid oxime, deoxycholic acid dienone, 3-keto-24-cholic alcohol and cholic acid amide showed best binding affinities for GR-LBD among tested compounds. The in silico molecular docking explanation is provided. SAR analysis showed that expansion of B and C steroid rings or attachment of heterocycle to C ring is not beneficial for binding; side chain should contain hydrogen donor group; the GR-LBD tolerate well different functionalities on C-3 position. These results provide valuable information toward synthesis of the new glucocorticoids based on bile acids.
Keywords: organic synthesis, docking studies, molecular modelling
Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 451-03-9/2021-14/200125
Show references
N. Sundahl, J. Bridelance, C. Libert, K. De Bosscher, I. M. Beck, Pharmacol. Ther. 152 (2015) 28 (https://doi.org/10.1016/j.pharmthera.2015.05.001)
F. Buttgereit, R. H. Straub, M. Wehling, G. R. Burmester, Arthritis Rheumatol. 50 (2004) 50 3408 (https://doi.org/10.1002/art.20583)
RECOVERY collaborative group*, N. Engl. J. Med. 384 (2021) 693 (https://doi.org/10.1056/NEJMoa2021436)
J. Souffriau, M. Eggermont, S. Van Ryckeghem, K. Van Looveren, L. Van Wyngene, E. Van Hamme, M. Vuylsteke, R. Beyaert, K. De Bosscher, C. Libert, Sci. Rep. 8 (2018) 12894. (https://doi.org/10.1038/s41598-018-31150-w)
J. Vandewalle, A. Luypaert, K. De Bosscher, C. Libert. Trends Endocrinol. Metab. 29 (2018) 42 (https://doi.org/10.1016/j.tem.2017.10.010)
A. Louw. Front. Immunol. 10 (2019) 1693 (https://doi.org/10.3389/fimmu.2019.01693)
E. Lontchi-Yimagou, E. Sobngwi, T. E. Matsha, A. P. Kengne. Curr. Diab. Rep. 13 (2013) 435 (https://doi.org/10.1007/s11892-013-0375-y)
P. S. Hench. Br. Med. J. 20 (1938) 394 (https://doi.org/10.1136/bmj.2.4050.394)
The Nobel Prize, https://www.nobelprize.org/prizes/medicine/1950/summary/ (20.06.2022.)
R. M. Gadaleta, M. Cariello, C. Sabbà, A. Moschetta, Biochim. Biophys. Acta 1851 (2015) 30 (https://doi.org/10.1016/j.bbalip.2014.08.005)
J. Hageman, H. Herrema, A. K. Groen, F. Kuipers, Arterioscler. Thromb. Vasc. Biol. 30 (2010) 1519 (https://doi.org/10.1161/ATVBAHA.109.197897)
A. Perino, K. Schoonjans, Trends. Pharmacol. Sci. 12 (2015) 847 (https://doi.org/10.1016/j.tips.2015.08.002)
B. Vasiljević, E. Petri, S. Bekić, A Ćelić, Lj. Grbović, K. Pavlović, RSC Med. Chem. 12 (2021) 278 (https://doi.org/10.1039/D0MD00311E)
L. Li, C. Liu, W. Mao, B. Tumen, P. Li, Molecules 24 (2019) 4513. (https://doi.org/10.3390/molecules24244513)
T. Takigawa, H. Miyazaki, M. Kinoshita, N. Kawarabayashi, K. Nishiyama, K. Hatsuse, S. Ono, D. Saitoh, S. Seki, J. Yamamoto, Am. J. Physiol. Gastrointest. Liver Physiol. 305 (2013) G427 (https://doi.org/10.1152/ajpgi.00205.2012)
M. Poša, S. Bjedov, V. Tepavčević, M. Mikulić, M. Sakač, J. Mol. Liq. 303 (2020) 112634 (https://doi.org/10.1016/j.molliq.2020.112634)
M. N. Iqbal, W. H. Elliott, Steroids 53 (1989) 413 (https://doi.org/10.1016/0039- 128X(89)90022-6)
R. Leppik, Steroids 41 (1983) 475 (https://doi.org/10.1016/0039-128X(83)90087-9)
R. Hüttenrauch, Arch. Pharm. Pharm. Med. Chem. 294 (1961) 366 (https://doi.org/10.1002/ardp.19612940608)
K. Tamaki, J. Biochem. 45 (1958) 299 (https://doi.org/10.1093/oxfordjournals.jbchem.a126869)
S. Bekić, M. Marinović, E. Petri, M. Sakač, A. Nikolić, V. Kojić, A. Ćelić, Steroids 130 (2018) 22 (https://doi.org/10.1016/j.steroids.2017.12.002)
S. Muddana, B. Peterson, Chembiochem. 4 (2003) 848 (https://doi.org/10.1002/cbic.200300606)
D. Gietz, A. St Jean, R. A. Woods, R. H. Schiestl, Nucleic. Acids. Res. 20 (1992) 1425. (https://doi.org/10.1093/nar/20.6.1425)
S. Dallakyan, A. J. Olson, Methods. Mol. Biol. 1263 (2015) 243 (https://doi.org/10.1007/978-1-4939-2269-7_19)
M. D. Hanwell, D. E. Curtis, D. C. Lonie, T. Vandermeerschd, E. Zurek, G. R. Hutchison, J. Cheminform. 17 (2012) (https://doi.org/10.1186/1758-2946-4-17)
R. K. Bledsoe, V. G. Montana, T. B. Stanley, C. J. Delves, C. J. Apolito, D. D. McKee, T. G. Consler, D. J. Parks, E. L. Stewart, T. M. Willson, M. H. Lambert, J. T. Moore, K. H. Pearce, H. E. Xu, Cell 110 (2002) 93 (https://doi.org/10.1016/s0092-8674(02)00817-6)
A. Pedretti, A. Mazzolari, S. Gervasoni, L. Fumagalli, G. Vistoli, Bioinformatics 37 (2021) 1174 (https://doi.org/10.1093/bioinformatics/btaa774)
PyMOL, http://www.pymol.org/pymol (15.09.2021.)
N. Meanwell, H. Roth, E. Smith, D. Wedding, and J. Kim Wright, J. Org. Chem. 56 (1991) 6897 (https://doi.org/10.1021/jo00024a036)
Y. Huang, J. Cui, S. Chen, C. Gan, Q. Yao, Q. Lin, Bioorg. Med. Chem. Lett. 23 (2013) 2265 (https://doi.org/10.1016/j.bmcl.2012.08.064)
H. H. Abdu-Allah, T. T. Chang, W. S. Li, Steroids 112 (2016) 54 (https://doi.org/10.1016/j.steroids.2016.04.013)
I. S. Zharinova, A. A. Bilyalova, S. I. Bezzubov, Acta Crystallogr., E 74 (2018) 816 (https://doi.org/10.1107/S2056989018007259)
M. I. Duran, C. González, A. Acosta, A. F. Olea, K. Díaz, L. Espinoza, Int. J. Mol. Sci. 8 (2017) 516 (https://doi.org/10.3390/ijms18030516)
M. Poša, V. Tepavčević, Lj. Grbović, M. Mikulić, K. Pavlović, J. Phys. Org. Chem. 34 (2021) e4133 (https://doi.org/10.1002/poc.4133)
D. Škorić, O. Klisurić, S. Jakimov, M. Sakač, J. Csanádi, Beilstein J. Org. Chem. 17 (2021) 2611 (https://doi.org/10.3762/bjoc.17.174)
D. Milijkovic, K. Kuhajda, J. Hranisavljevic, J. Chem. Res. 2 (1996) 106 (https://open.uns.ac.rs/handle/123456789/12941)
G. M. Morris, R. Huey, W. Lindstrom, M. Sanner, R. Belew, D. Goodsell, A. Olson, J. Comput. Chem. 16 (2009) 2785 (https://doi.org/10.1002/jcc.21256)
T. Mitić, S. Shave, N. Semjonous, I. McNae, D. Cobice, G. Lavarey, S. Webster, P. Hadkoe, B. Walker, R. Andrew, Biochem. Pharmacol. 86 (2013) 146 (https://doi.org/10.1016/j.bcp.2013.02.002)
U. Lind, P. Greenidge, M. Gillner, K. F. Koehler, A. Wright, J. Carlstedt-Duke, J. Biol. Chem. 275 (2000) 19041 (https://doi.org/10.1074/jbc.M000228200).