Ecdysteroids: A novel class of anabolic agents?

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Abstract

Increasing numbers of dietary supplements with ecdysteroids are marketed as “natural anabolic agents”. Results of recent studies suggested that their anabolic effect is mediated by estrogen receptor (ER) binding. Within this study the anabolic potency of ecdysterone was compared to well characterized anabolic substances. Effects on the fiber sizes of the soleus muscle in rats as well the diameter of C2C12 derived myotubes were used as biological readouts. Ecdysterone exhibited a strong hypertrophic effect on the fiber size of rat soleus muscle that was found even stronger compared to the test compounds metandienone (dianabol), estradienedione (trenbolox), and SARM S 1, all administered in the same dose (5 mg/kg body weight, for 21 days). In C2C12 myotubes ecdysterone (1 µM) induced a significant increase of the diameter comparable to dihydrotestosterone (1 µM) and IGF 1 (1.3 nM). Molecular docking experiments supported the ERβ mediated action of ecdysterone. To clarify its status in sports, ecdysterone should be considered to be included in the class “S1.2 Other Anabolic Agents” of the list of prohibited substances of the World Anti-Doping Agency.

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Improved protein-ligand docking using GOLD.

Marcel Verdonk, Jason Cole, Michael J Hartshorn … (2003)

The Chemscore function was implemented as a scoring function for the protein-ligand docking program GOLD, and its performance compared to the original Goldscore function and two consensus docking protocols, "Goldscore-CS" and "Chemscore-GS," in terms of docking accuracy, prediction of binding affinities, and speed. In the "Goldscore-CS" protocol, dockings produced with the Goldscore function are scored and ranked with the Chemscore function; in the "Chemscore-GS" protocol, dockings produced with the Chemscore function are scored and ranked with the Goldscore function. Comparisons were made for a "clean" set of 224 protein-ligand complexes, and for two subsets of this set, one for which the ligands are "drug-like," the other for which they are "fragment-like." For "drug-like" and "fragment-like" ligands, the docking accuracies obtained with Chemscore and Goldscore functions are similar. For larger ligands, Goldscore gives superior results. Docking with the Chemscore function is up to three times faster than docking with the Goldscore function. Both combined docking protocols give significant improvements in docking accuracy over the use of the Goldscore or Chemscore function alone. "Goldscore-CS" gives success rates of up to 81% (top-ranked GOLD solution within 2.0 A of the experimental binding mode) for the "clean list," but at the cost of long search times. For most virtual screening applications, "Chemscore-GS" seems optimal; search settings that give docking speeds of around 0.25-1.3 min/compound have success rates of about 78% for "drug-like" compounds and 85% for "fragment-like" compounds. In terms of producing binding energy estimates, the Goldscore function appears to perform better than the Chemscore function and the two consensus protocols, particularly for faster search settings. Even at docking speeds of around 1-2 min/compound, the Goldscore function predicts binding energies with a standard deviation of approximately 10.5 kJ/mol. Copyright 2003 Wiley-Liss, Inc.

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Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes.

Jean-Louis Pons, Abdelhay Boulahtouf, Vanessa Delfosse … (2012)

Bisphenol A (BPA) is an industrial compound and a well known endocrine-disrupting chemical with estrogenic activity. The widespread exposure of individuals to BPA is suspected to affect a variety of physiological functions, including reproduction, development, and metabolism. Here we report that the mechanisms by which BPA and two congeners, bisphenol AF and bisphenol C (BPC), bind to and activate estrogen receptors (ER) α and β differ from that used by 17β-estradiol. We show that bisphenols act as partial agonists of ERs by activating the N-terminal activation function 1 regardless of their effect on the C-terminal activation function 2, which ranges from weak agonism (with BPA) to antagonism (with BPC). Crystallographic analysis of the interaction between bisphenols and ERs reveals two discrete binding modes, reflecting the different activities of compounds on ERs. BPA and 17β-estradiol bind to ERs in a similar fashion, whereas, with a phenol ring pointing toward the activation helix H12, the orientation of BPC accounts for the marked antagonist character of this compound. Based on structural data, we developed a protocol for in silico evaluation of the interaction between bisphenols and ERs or other members of the nuclear hormone receptor family, such as estrogen-related receptor γ and androgen receptor, which are two known main targets of bisphenols. Overall, this study provides a wealth of tools and information that could be used for the development of BPA substitutes devoid of nuclear hormone receptor-mediated activity and more generally for environmental risk assessment.

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Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity.

Karine Pereira de Jésus-Tran, Pierre-Luc Côté, Line Cantin … (2006)

Androgens exert their effects by binding to the highly specific androgen receptor (AR). In addition to natural potent androgens, AR binds a variety of synthetic agonist or antagonist molecules with different affinities. To identify molecular determinants responsible for this selectivity, we have determined the crystal structure of the human androgen receptor ligand-binding domain (hARLBD) in complex with two natural androgens, testosterone (Testo) and dihydrotestosterone (DHT), and with an androgenic steroid used in sport doping, tetrahydrogestrinone (THG), at 1.64, 1.90, and 1.75 A resolution, respectively. Comparison of these structures first highlights the flexibility of several residues buried in the ligand-binding pocket that can accommodate a variety of ligand structures. As expected, the ligand structure itself (dimension, presence, and position of unsaturated bonds that influence the geometry of the steroidal nucleus or the electronic properties of the neighboring atoms, etc.) determines the number of interactions it can make with the hARLBD. Indeed, THG--which possesses the highest affinity--establishes more van der Waals contacts with the receptor than the other steroids, whereas the geometry of the atoms forming electrostatic interactions at both extremities of the steroid nucleus seems mainly responsible for the higher affinity measured experimentally for DHT over Testo. Moreover, estimation of the ligand-receptor interaction energy through modeling confirms that even minor modifications in ligand structure have a great impact on the strength of these interactions. Our crystallographic data combined with those obtained by modeling will be helpful in the design of novel molecules with stronger affinity for the AR.

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Author and article information

Journal

Journal ID (nlm-ta): Biol Sport

Journal ID (iso-abbrev): Biol Sport

Journal ID (publisher-id): JBS

Title: Biology of Sport

Publisher: Institute of Sport in Warsaw

ISSN (Print): 0860-021X

ISSN (Electronic): 2083-1862

Publication date (Electronic): 15 March 2015

Publication date (Print): June 2015

Volume: 32

Issue: 2

Pages: 169-173

Affiliations

[1 ]Institute of Pharmaceutical and Medicinal Chemistry, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Germany

[2 ]Laboratorio Antidoping, Federazione Medico Sportiva Italiana, Rome, Italy

[3 ]Department of Cellular and Molecular Sports Medicine, Institute of Cardiovascular Research and Sports Medicine, German Sport University Cologne, Germany

Author notes

Corresponding author: Maria Kristina Parr, Freie Universität Berlin, Institute of Pharmacy, Königin-Luise-Str. 2 + 4, 14195 Berlin, Germany. fon +49(0)30 838 57 686, fax +49(0)30 838 457 686. E-mail: maria.parr@ 123456fu-berlin.de

Article

Publisher ID: 1144420

DOI: 10.5604/20831862.1144420

PMC ID: 4447764

SO-VID: 5cf17b3f-2293-427f-9792-2216e009c7b6

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 09 February 2015

Date revision received : 23 February 2015

Date accepted : 27 February 2015

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Ecdysteroids: A novel class of anabolic agents?

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Most cited references 21

Improved protein-ligand docking using GOLD.

Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes.

Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity.

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