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Alvarez, L.D.; Dansey, M.V.; Martí, M.A.; Bertucci, P.Y.; Di Chenna, P.H.; Pecci, A.; Burton, G. "Biological activity and ligand binding mode to the progesterone receptor of A-homo analogues of progesterone" (2011) Bioorganic and Medicinal Chemistry. 19(5):1683-1691
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Abstract:

The biological activity of two seven-membered A-ring (A-homo) analogues of progesterone was evaluated by transactivation assays in Cos-1 cells and by determination of Bcl-x L expression levels in T47D cells. The results show that both compounds act as selective progesterone receptor (PR) agonists but lack mineralocorticoid receptor (MR) activity. Molecular modelling using semiempirical AM1 and ab initio HF/6-31G calculations, showed that the A-ring of the A-homo steroids may adopt five different conformations, although only three correspond to low energy conformers. The low energy conformers of each analogue were introduced into the ligand binding pocket of the PR ligand binding domain (LBD) obtained from the PR LBD-progesterone crystal structure. The steroid binding mode was then analyzed using 10 ns of molecular dynamics (MD) simulation. The PR LBD-progesterone complex was also simulated as a control system. The MD results showed that both A-homo steroids have one conformer that may be properly recognized by the PR, in agreement with the observed progestagen activity. Moreover, the simulation revealed the importance of a water molecule in the formation of a hydrogen bonding network among specific receptor residues and the steroid A-ring carbonyl. © 2011 Elsevier Ltd. All rights reserved.

Registro:

Documento: Artículo
Título:Biological activity and ligand binding mode to the progesterone receptor of A-homo analogues of progesterone
Autor:Alvarez, L.D.; Dansey, M.V.; Martí, M.A.; Bertucci, P.Y.; Di Chenna, P.H.; Pecci, A.; Burton, G.
Filiación:Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria, Pabellón 2, C1428EGA Buenos Aires, Argentina
IFIBYNE (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria, Pabellón 2, C1428EGA Buenos Aires, Argentina
Departamento de Química Biológica (UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, C1428EGA Buenos Aires, Argentina
INQUIMAE (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, C1428EGA Buenos Aires, Argentina
Palabras clave:A-Homo pregnane; Molecular dynamics; Progestagen; Progesterone receptor; 5 pregnene 3,20 dione; 5 pregnene 4,20 dione; complementary DNA; gestagen; ligand; mineralocorticoid receptor; progesterone; progesterone receptor; protein bcl xl; RNA; unclassified drug; animal cell; article; biological activity; breast cancer; cancer cell; cell strain COS1; crystal structure; hormone receptor interaction; hydrogen bond; ligand binding; molecular dynamics; molecular model; nonhuman; quantum mechanics; structure activity relation; Animals; Cercopithecus aethiops; COS Cells; Ligands; Models, Molecular; Molecular Dynamics Simulation; Pregnanes; Progesterone; Receptors, Progesterone
Año:2011
Volumen:19
Número:5
Página de inicio:1683
Página de fin:1691
DOI: http://dx.doi.org/10.1016/j.bmc.2011.01.033
Título revista:Bioorganic and Medicinal Chemistry
Título revista abreviado:Bioorg. Med. Chem.
ISSN:09680896
CODEN:BMECE
CAS:RNA, 63231-63-0; progesterone, 57-83-0; protein bcl xl, 151033-38-4; Ligands; Pregnanes; Progesterone, 57-83-0; Receptors, Progesterone
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v19_n5_p1683_Alvarez

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Citas:

---------- APA ----------
Alvarez, L.D., Dansey, M.V., Martí, M.A., Bertucci, P.Y., Di Chenna, P.H., Pecci, A. & Burton, G. (2011) . Biological activity and ligand binding mode to the progesterone receptor of A-homo analogues of progesterone. Bioorganic and Medicinal Chemistry, 19(5), 1683-1691.
http://dx.doi.org/10.1016/j.bmc.2011.01.033
---------- CHICAGO ----------
Alvarez, L.D., Dansey, M.V., Martí, M.A., Bertucci, P.Y., Di Chenna, P.H., Pecci, A., et al. "Biological activity and ligand binding mode to the progesterone receptor of A-homo analogues of progesterone" . Bioorganic and Medicinal Chemistry 19, no. 5 (2011) : 1683-1691.
http://dx.doi.org/10.1016/j.bmc.2011.01.033
---------- MLA ----------
Alvarez, L.D., Dansey, M.V., Martí, M.A., Bertucci, P.Y., Di Chenna, P.H., Pecci, A., et al. "Biological activity and ligand binding mode to the progesterone receptor of A-homo analogues of progesterone" . Bioorganic and Medicinal Chemistry, vol. 19, no. 5, 2011, pp. 1683-1691.
http://dx.doi.org/10.1016/j.bmc.2011.01.033
---------- VANCOUVER ----------
Alvarez, L.D., Dansey, M.V., Martí, M.A., Bertucci, P.Y., Di Chenna, P.H., Pecci, A., et al. Biological activity and ligand binding mode to the progesterone receptor of A-homo analogues of progesterone. Bioorg. Med. Chem. 2011;19(5):1683-1691.
http://dx.doi.org/10.1016/j.bmc.2011.01.033