Professional Documents
Culture Documents
Abstract
Purpose: To undertake an in silico assessment of rocaglamide as a potential drug therapy for
periodontitis (dental arthritis).
Method: Lamarckian algorithm-based automated docking approach using AutoDock4.2 tool was
applied for calculating the best possible binding mode of rocaglamide to IL-23p19 and IL-17, the targets
of anti-inflammatory drugs in periodontal disease.
Results: The top two interactions of rocaglamide with IL-17 (ΔG = -5.45 and -4.83 kcal/mol) were more
spontaneous, and the physical interactions (two hydrogen bonds and one π-πbond) generated in the
two IL-17- rocaglamide complexes were higher in number than in IL-23p14-rocaglamide complexes.
Conclusion: In silico analysis of rocaglamide, a known antimicrobial and anti-inflammatory agent, is a
promising natural candidate for periodontitis therapy, and should be further subjected to in vitro and in
vivo anti-periodontitis investigations.
This is an Open Access article that uses a funding model which does not charge readers or their institutions
for access and distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0) and the Budapest Open Access Initiative
(http://www.budapestopenaccessinitiative.org/read), which permit unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited.
Tropical Journal of Pharmaceutical Research is indexed by Science Citation Index (SciSearch), Scopus,
International Pharmaceutical Abstract, Chemical Abstracts, Embase, Index Copernicus, EBSCO, African
Index Medicus, JournalSeek, Journal Citation Reports/Science Edition, Directory of Open Access Journals
(DOAJ), African Journal Online, Bioline International, Open-J-Gate and Pharmacy Abstracts
Compound selection
Figure 1: Protein sub-networks of IL-17A and IL-23A
Rocaglamide, a natural compound was retrieved (queried proteins) with IL-6, NFKB1A and some
important proteins involved in arthritis (only significant
from PubChem compound database. The SDF
sub-networks are shown)
format of the compound was retrieved bearing
CID 331783, and it was converted to PDF prior to The 3D structure of the protein retrieved from
further studies, using Discovery Studio.
protein database was trimmed to suit the
experimental design using Discovery studio. The
Molecular docking analysis modification of both proteins are shown Figure
2a (IL-23p19) and Figure 2b (IL-17). The trimmed
Molecular docking analysis of the IL-23p19 and structures were used for molecular docking, and
IL-17 proteins with rocaglamide was done using blind docking approach was used to look into the
Auto Dock4.2tool [19]. The Auto Dock4.2tool possibility of successful docking of rocaglamide
calculates energy values by classification of onto the two selected cytokines. Table 1 shows
energies as internal energy and torsional free the Gibbs free energy of the top two poses of
energy as in Eq 1. each complex.
Trop J Pharm Res, January 2018; 17(1): 42
Yan et al
Table 2: Auto dock analysis of the top two poses of protein-rocaglamide complexes.
CONCLUSION
The results obtained in this study suggest that
rocaglamide may have potent anti-periodontitis
effects. Being an anti-inflammatory drug with
Figure 5: Two dimensional representations of the top known anti-microbial activity, these findings
four poses. (a) and (b) show the top two poses of IL- make it potentially suitable for the development
23p14, while (c) and (d) show IL-17 interactions with of a new drug for treating periodontitis, a disease
rocaglamide in which microbial infection and inflammation are
common challenges.
LYS-38, SER-41, TYR-43, TYR-44, SER-47,
TRP-51, LEU-53, ILE-92, VAL-119, GLY-120, DECLARATIONS
and CYS-121. Two rocaglamide atoms, O-6 and
H-41formed bond with TYR-44 andVAL-119, Acknowledgement
respectively with bond lengths of 3.16 and 2.29
Ǻ, respectively. Rather than forming two The authors would like to thank the management
hydrogen bond interactions, the complex
of Jining No.1 People’s Hospital for providing the
rocaglamide-IL-17 complex exhibited two pi-pi
infrastructure for this research work.
interactions, as shown in Figure 5 (c). The
second best pose of IL-17 in the rocaglamide-IL-
Conflict of interest
17 complex had a ΔG of -4.83 kcal/mol. It also
exhibited two hydrogen bond interactions in the
binding pocket. The binding pocket in this case There are no competing interests with regard to
contained the following amino acids: THR-35, this work.
PRO-37, LYS-38, SER-40, SER-41, TYR-44,
TRP-51, VAL-119 and GLY-120.The O-6and O- Contribution of authors
7atoms of rocaglamide interacted with SER-40
and TRP-51, with bond lengths of 2.7 and 2.8 Ǻ, We declare that this work was done by the
respectively. Based on binding energies, authors named in this article and all liabilities
rocaglamide showed the least binding energy of - pertaining to claims relating to the content of this
0.63kcal/mole with IL-23p14. article will be borne by the authors. YPY and
XQZ carried out the study; XKW analyzed the
Various conceptual models spanning over five results, while LXL and JJM Developed the
decades have been proposed to describe the concept and wrote up the manuscript. JJM
etiology of periodontitis. Two factors, microbial reviewed the manuscript.
infection and inflammation, are thought to play
pivotal roles in the shift from the healthy state to REFERENCES
periodontitis. Thus, the development of strategies
is based on these two factors. Compounds of
1. Newman, MG, Henry T, Perry RK, Fermin AC. Carranza's
natural origin are invaluable in novel drug
clinical periodontology. Elsevier Health Sciences, USA
discovery, and many natural compounds have
2011.
been reported to have dual functions [17,20]. The
2. Slots J, Listgarten MA. Bacteroides gingivalis,
present study was focused on a compound with
Bacteroides intermedius and Actinobacillus
antimicrobial and anti-inflammatory properties.
This was based on knowledge from Traditional actinomycetemcomitans in human periodontal diseases.
Chinese Medicine. Rocaglamide, a flavagline of J Clin Periodontol 1988; 15(2): 85-93.
natural origin, is a known traditional Chinese
3. Brandtzaeg P, Kraus FW. Auto- immunity and periodontal 13. Sigusch B, Klinger G, Glockmann E, Simon HU. Early-
disease. Odontol T 1965; 73: 281-393. onset and adult periodontitis associated with abnormal
4. Boman HG. Innate immunity and the normal microfora. cytokine production by activated T lymphocytes. J
Immunol Rev 2000; 173: 5-16. Periodontol 1998; 69: 1098-1104.
5. Ji S, Hyun J, Park E, Lee BL, Kim KK, Choi Y. 14. Bartova J, Kratka-Opatrna Z, Prochazkova J, Krejsa O,
Susceptibility of various oral bacteria to antimicrobial Duskova J, Mrklas L, Tlaskalova H and Cukrowska B.
peptides and to phagocytosis by neutrophils. J Th1 and Th2 cytokine profile in patients with early onset
Periodont Res 2007; 42(5): 410-419. periodontitis and their healthy siblings. Mediators
6. Kornman KS. Mapping the pathogenesis of periodontitis: Inflamm 2000; 9:115-120
a new look. J Periodontol 2008; 79(8): 1560-1568. 15. Feldmann M, Steinman L. Design of effective
7. Ivanyi L, Lehner T. Stimulation of lymphocyte immunotherapy for human autoimmunity. Nature 2005;
transformation by bacterial antigens in patients with 435(7042): 612-619.
periodontal disease. Arch Oral Biol 1970; 15: 1089- 16. Rayavarapu S. Synthesis of Putrescine Bisamides as
1096. Antimicrobial and Anti-Inflammatory Agents. Med chem.
8. Gemmell E, Yamazaki K, Seymour G. The role of T cells 2014; 4: 367-372.
in periodontal disease: homeostasis and autoimmunity. 17. Zhou W, Cai JF, Yuan F, Ma M, & Yin F. In silico
Periodonto l2000; 2007; 43: 14-40. targeting of interleukin-6 by natural compounds.
9. Kinane DF, Demuth DR, Gorr SU, Hajishengallis GN, Bangladesh Journal of Pharmacology 2014; 9(3): 371-
Martin MH. Human variability in innate immunity. 376.
Periodontol 2000; 2007; 45:14-34. 18. Gerhardt, Abbott WM, Hargreaves D, Pauptit RA, Davies
10. Manhart SS, Reinhardt RA, Payne JB, Seymour GJ, RA, Needham MRC, Langham C, Barker W, Aziz A,
Gemmell E, Dyer JK, Petro TM. Gingival cell IL-2 and Snow MJ, Dawson S. Structure of IL-17A in complex
IL-4 in early-onset periodontitis. J Periodontol 1994; 65: with a potent, fully human neutralizing antibody. J Mol
807-813. Biol 2009; 394(5): 905-921.
11. Aoyagi T, Sugawara-Aoyagi M, Yamazaki K, Hara K. 19. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK,
Interleukin 4 (IL-4) and IL-6-producing memory T-cells in Goodsell DS, Olson AJ. AutoDock4 and
peripheral blood and gingival tissue in periodontitis AutoDockTools4: Automated docking with selective
patients with high serum antibody titers to receptor flexibility. J Comput Chem 2009; 30(16): 2785-
Porphyromonas gingivalis. Oral Microbiol Immunol 2791.
1995; 10: 304-310. 20. Zhou X, Lin J, Yin Y, Zhao J, Sun X, Tang K.
12. Tokoro Y, Matsuki Y, Yamamoto T, Suzuki T, Hara K. Ganodermataceae: natural products and their related
Relevance of local Th2-type cytokine mRNA expression pharmacological functions. Am J Chin Med 2007;
in immunocompetent infiltrates in inflamed gingival 35(04): 559-574.
tissue to periodontal diseases. Clin Exp Immunol 1997;
107: 166-174.