Computational Binding Study Hints at Ecdysone 20-Mono-Oxygenase as the Hitherto Unknown Target for Ring C-Seco Limonoid-Type Insecticides.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

Insecticides*/pharmacology ; Limonins*/pharmacology; Oxygenases ; Ecdysone ; Molting

The insecticidal property of ring C-seco limonoids has been discovered empirically and the target protein identified, but, to date, the molecular mechanism of action has not been described at the atomic scale. We elucidate on computational grounds whether nine C-seco limonoids present sufficiently high affinity to bind specifically with the putative target enzyme of the insects (ecdysone 20-monooxygenase). To this end, 3D models of ligands and the receptor target were generated and their interaction energies estimated by docking simulations. As a proof of concept, the tetrahydro-isoquinolinyl propenamide derivative QHC is the reference ligand bound to aldosterone synthase in the complex with PDB entry 4ZGX. It served as the 3D template for target modeling via homology. QHC was successfully docked back to its crystal pose in a one-digit nanomolar range. The reported experimental binding affinities span over the nanomolar to lower micromolar range. All nine limonoids were found with strong affinities in the range of -9 < ΔG < -13 kcal/mol. The molt hormone ecdysone showed a comparable ΔG energy of -12 kcal/mol, whereas -11 kcal/mol was the back docking result for the liganded crystal 4ZGX. In conclusion, the nine C-seco limonoids were strong binders on theoretical grounds in an activity range between a ten-fold lower to a ten-fold higher concentration level than insecticide ecdysone with its known target receptor. The comparable or even stronger binding hints at ecdysone 20-monooxygenase as their target biomolecule. Our assumption, however, is in need of future experimental confirmation before conclusions with certainty can be drawn about the true molecular mechanism of action for the C-seco limonoids under scrutiny.

J Biol Chem. 2017 Jun 30;292(26):10767-10778. (PMID: 28539365)
Plants (Basel). 2021 Feb 09;10(2):. (PMID: 33572083)
J Comput Chem. 2009 Dec;30(16):2785-91. (PMID: 19399780)
Chem Rev. 2011 Nov 9;111(11):7437-522. (PMID: 21894902)
Nucleic Acids Res. 2000 Jan 1;28(1):235-42. (PMID: 10592235)
Science. 2000 Mar 3;287(5458):1615-22. (PMID: 10698731)
PLoS One. 2016 Dec 1;11(12):e0167485. (PMID: 27907120)
Mol Endocrinol. 2013 Feb;27(2):315-24. (PMID: 23322723)
ACS Chem Biol. 2016 Sep 16;11(9):2642-54. (PMID: 27420774)
Clin Chim Acta. 2005 Sep;359(1-2):1-26. (PMID: 15936746)
Plants (Basel). 2023 Feb 21;12(5):. (PMID: 36903853)
Biol Pharm Bull. 2006 Feb;29(2):191-201. (PMID: 16462017)
Biochemistry. 2009 Jun 9;48(22):4762-71. (PMID: 19397311)
J Comput Chem. 2004 Oct;25(13):1605-12. (PMID: 15264254)
Curr Med Chem. 2020;27(1):54-77. (PMID: 31272346)
Electrophoresis. 1997 Dec;18(15):2714-23. (PMID: 9504803)
Drug Discov Today. 2014 Jul;19(7):905-11. (PMID: 24642031)
J Biol Chem. 2012 Dec 28;287(53):44581-91. (PMID: 23118231)
Philos Trans R Soc Lond B Biol Sci. 2011 Jul 12;366(1573):1987-98. (PMID: 21624919)
Molecules. 2016 Nov 13;21(11):. (PMID: 27845763)
Bioorg Med Chem. 2009 Jun 15;17(12):4096-105. (PMID: 19112026)
Biomedicines. 2021 Apr 22;9(5):. (PMID: 33922200)
Biochemistry. 2004 Jul 27;43(29):9487-94. (PMID: 15260491)
J Med Chem. 2015 Oct 22;58(20):8054-65. (PMID: 26403853)
J Biol Chem. 2015 Sep 25;290(39):23916-34. (PMID: 26269599)
Nucleic Acids Res. 2018 Jul 2;46(W1):W296-W303. (PMID: 29788355)
Plants (Basel). 2020 Jan 22;9(2):. (PMID: 31979199)
J Chem Inf Model. 2014 Mar 24;54(3):978-86. (PMID: 24512031)
Front Physiol. 2013 Dec 20;4:359. (PMID: 24391591)
J Biol Chem. 2015 Feb 20;290(8):5092-5104. (PMID: 25555909)
J Biol Chem. 2015 Feb 6;290(6):3248-68. (PMID: 25533464)
Mol Biol Evol. 2016 Jul;33(7):1870-4. (PMID: 27004904)
Comput Appl Biosci. 1992 Jun;8(3):275-82. (PMID: 1633570)
J Steroid Biochem Mol Biol. 2018 Jul;181:11-19. (PMID: 29476820)

Keywords: C-seco limonoid; docking; ecdysone; ecdysone 20-monooxygenase; insecticide; molecular mechanism

EC 1.13.- (Oxygenases)
0 (Insecticides)
3604-87-3 (Ecdysone)
0 (Limonins)

Date Created: 20240413 Date Completed: 20240415 Latest Revision: 20240415

20240415

PMC11013123

10.3390/molecules29071628

38611907