Molecular Docking of Azadirachtin in Nuclear Ecdysone Receptor

Author(s): Daniel Augusto Barra de Oliveira* , Alcedino Venancio da Silva , Edenilson dos Santos Niculau .

Journal Name: Current Physical Chemistry

Volume 9 , Issue 1 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: The azadirachtin is a triterpenoid associated with growth inhibition in several kinds of insects which cause epidemic diseases like Dengue, Chikungunya and Malaria. Azadirachtin acts by inhibiting the Ecdysone Receptor (EcR), which is responsible from larvae phase in insects. However, the interaction between the azadirachtin molecule and the Ecdysone Receptor is unknown. In this work, we used the program Dock Thor to generate several azadirachtin conformations inside the EcR binding site. The ten most stable conformations were optimized with the ONIOM approach present in the Gaussian 09 program. The interaction energy was calculated between the azadirachtin molecule and EcR receptor. Theoretical calculation shows that the azadirachtin molecule interacts with the same amino acids present in the ecdysone EcR interaction. These results will be useful to design new EcR inhibitors, which can be used in the control of some diseases based on insect proliferations.

Objective: To understand the interaction between the natural insecticide azadirachtin and the Ecdysone Receptor.

Methods: A combination of Dock Thor program with QM-MM calculation was used in order to obtain the most favorable molecular structures.

Results: The hydrogens bond obtained by Dock Thor Program combined with QM-MM calculation suggest the azadirachtin interact with EcR in the same way that ecdysone molecule.

Conclusion: The interaction mode that the molecule azadirachtin inhibits EcR in order to avoid insect proliferation was described.

Keywords: Azadiracthin, ecdysone, EcR ecdysone receptor, molecular docking, amino acids, inhibotrs.

[1]
Koelle, M.R.; Talbot, W.S.; Segraves, W.A.; Bender, M.T.; Cherbas, P.; Hogness, D.S. The Drosophila EcR gene encodes an ecdysone receptor, a new member of the steroid receptor superfamily. Cell, 1991, 67, 59-77.
[2]
Oro, A.E.; McKeown, M.; Evans, R.M. Relationship between the product of the Drosophila ultraspiracle locus and the vertebrate retinoid X receptor. Nature, 1990, 347, 298-301.
[3]
Henrich, V.C.; Sliter, T.J.; Lubahn, D.B.; MacIntyre, A.; Gilbert, L.I. A steroid/thyroid hormone receptor superfamily member in Drosophila melanogaster that shares extensive sequence similarity with a mammalian homologue. Nucleic Acids Res., 1990, 18, 4143-4148.
[4]
Shea, M.J.; King, D.L.; Conboy, M.J.; Mariani, B.D.; Kafatos, F.C. Proteins that bind to Drosophila chorion cis-regulatory elements: a new C2H2 zinc finger protein and a C2C2 steroid receptor-like component. Genes Dev., 1990, 4, 1128-1140.
[5]
Yao, T.P.; Forman, B.M.; Jiang, Z.; Cherbas, L.; Chen, J.D.; McKeown, M.; Cherbas, P.; Evans, R.M. Functional ecdysone receptor is the product of EcR and ultra spiracle genes. Nature, 1993, 366, 476-479.
[6]
Riddiford, L.M.; Cherbas, P.; Truman, J.W. Ecdysone receptors and their biological actions. Vitam. Horm., 2000, 60, 1-73.
[7]
Cynthia, L.; Elisabeth, M.; Paulien, P.; Jozef, B. The ecdysone receptor complex is essential for the reproductive success in the female desert locust, Schistocerca gregaria. Sci. Rep., 2019, 9, 15.
[8]
Farkaš, R.; Sláma, K. Insect biochem. Effect of bisacylhydrazine ecdysteroid mimics (RH-5849 and RH-5992) on chromosomal puffing, imaginal disc proliferation and pupariation in larvae of Drosophila melanogaster. Mol. Biol., 1999, 29, 1015-1027.
[9]
Carmichael, J.A.; Lawrence, M.C.; Graham, L.D.; Pilling, P.A.; Epa, V.C.; Noyce, L.; Lovrecz, G.; Winkler, D.A.; Pawlak-Skrzecz, A.; Eaton, R.E.; Hannan, G.N.; Hill, R.J. The X-ray structure of a hemipteran ecdysone receptor ligand-binding domain: comparison with a lepidopteran ecdysone receptor ligand-binding domain and implications for insecticide design. J. Biol. Chem., 2005, 280, 22258-22269.
[10]
Yadav, R.P.; Ibrahim, K.S.; Gurusubramanian, G.; Kumar, N.S. In silico docking studies of non-azadirachtin limonoids against ecdysone receptor of Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae). Med. Chem. Res., 2015, 24, 2621-2631.
[11]
Schmutterer, H. The neem tree: Azadirachta indica A. Juss and other meliaceous plants: sources of unique natural products for integrated pest management, medicine, industry, and other purposes; Wiley: New York, 1995, pp. 1-696.
[12]
Gill, J.S.; Lewis, C.T. Systemic action of an insect feeding deterrent. Nature, 1971, 232, 402-403.
[13]
Ruscoe, C.N.E. Growth disruption effects of an insect antifeedant. Nat. New Biol., 1972, 236, 159-160.
[14]
Butterworth, J.H.; Morgan, E.D. Isolation of a substance that suppresses feeding in locusts. Chem. Commun., 1968, 1, 23.
[15]
Smith, S.L.; Mitchell, M.J. Effects of Azadirachtin on insect cytochrome P-450 dependent ecdysone 20-monooxygenase activity. Biochem. Biophys. Res. Commun., 1988, 154, 559-563.
[16]
Mitchell, M.J.; Smith, S.L.; Johnson, S.; Morgan, D. Effects of the neem tree compounds Azadirachtin, Salannin, Nimbin, and 6-Desacetylnimbin on ecdysone 20-monooxygenase activity. Arch. Insect Biochem. Physiol., 1997, 35, 199-209.
[17]
Boulahbel, B.; Aribi, N.; Kilani-Morakchi, S.; Soltani, N. Insecticidal activity of Azadirachtin on Drosophila melanogaster and recovery of normal status by exogenous 20-hydroxyecdysone. Afr. Entomol., 2015, 23(1), 224-234.
[18]
Nunes, M.L.; Carlini, C.R.; Marinowic, D.; Neto, F.K.; Fiori, H.H.; Scotta, M.C.; Zanella, P.L.Á.; Soder, R.B.; da Costa, J.C. Microcephaly and Zika virus: a clinical and epidemiological analysis of the current outbreak in Brazil. J. Pediatr., 2016, 92, 230-240.
[19]
Maria-Lucia, C.L.; Alessandra, L.C.; Paloma, A.V.; Tania, B.T.; Adriana, S.F.; Suely, F.P.; Onildo, T.S.; Clara, L.R.; Cristiana, M.N.C. Clinical, neuroimaging, and neurophysiological findings in children with microcephaly related to congenital Zika virus infection. Int. J. Environ. Res. Public Health, 2019, 16(3), 309-317.
[20]
Kraeme, M.U.G.; Cummings, D.A.T.; Funk, S.R.; Reiner, C. Reconstruction and prediction of viral disease epidemics. Epidemiol. Infect., 2019, 147e34
[21]
de Magalhães, C.S.; Barbosa, H.J.C.; Dardene, L.E. A genetic algorithm for the ligand-protein docking problem. Genet. Evol. Comput., 2004, 2004, 368-379.
[22]
Elton, A.S.C.; Daniel, A.B.O.; Sergio, A.S.; Farias, R.G.; João, B.L.M. Structure and electronic properties of azadiracthin. J. Mol. Model., 2014, 20, 1-7.
[23]
Arêas, E.P.G.; Pascutti, P.G.; Schreier, S.; Mundim, K.C.; Bisch, P.M. Molecular dynamics simulations of signal sequences at a membrane/water interface. J. Phys. Chem., 1995, 99, 14885-14892.
[24]
Pascutti, P.G.; El-Jaik, L.J.; Mundim, K.C.; Ito, A.S.; Bisch, P.M. Molecular dynamics simulation of α-melanocyte stimulating hormone in a water-membrane model interface. Eur. Biophys. J., 1999, 28, 499-509.
[25]
Pascutti, P.G.; Mundim, K.C.; Ito, A.S.; Bisch, P.M. Polarization effects on peptide conformations at water-membrane interface by molecular dynamics simulations. J. Comput. Chem., 1999, 20, 971-982.
[26]
Frisch, M.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A. Others, Gaussian 09, revision a. 02, gaussian, Inc., Wallingford, CT,, 2009.
[27]
Chai, J.D.; Head-Gordon, M. Long-range corrected double-hybrid density functionals. J. Chem. Phys., 2008, 128084106
[28]
Kabaleeswaran, V.; Rajan, S.S.; Govindachari, T.R.; Gopalakrishnan, G. Crystal and molecular structure of azadirachtin-A. Curr. Sci., 1994, 66, 362-364.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 9
ISSUE: 1
Year: 2019
Page: [50 - 57]
Pages: 8
DOI: 10.2174/1877946809666190320141833

Article Metrics

PDF: 26
HTML: 1