Title:Computational Study of the Binding Modes of Diverse DPN Analogues on Estrogen Receptors (ER) and the Biological Evaluation of a New Potential Antiestrogenic Ligand
VOLUME: 18 ISSUE: 11
Author(s):M. Martinez-Archundia*, J.B. García-Vázquez, B. Colin-Astudillo, M. Bello, B. Prestegui-Martel, A. Chavez-Blanco, A. Dueñas-González, M.J. Fragoso-Vázquez, J. Mendieta-Wejebe, E. Abarca-Rojano, D. Ordaz-Rosado, R. García-Becerra, D. Castillo-Bautista and J. Correa Basurto
Affiliation:Laboratorio de Modelado Molecular, Bioinformatica y diseno de farmacos, Seccion de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Díaz Miron S/N, Col, Casco de Santo Tomas, Mexico City, 11340 MX, Laboratorio de Modelado Molecular, Bioinformatica y diseno de farmacos, Seccion de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Díaz Miron S/N, Col, Casco de Santo Tomas, Mexico City, 11340 MX, Laboratorio de Modelado Molecular, Bioinformatica y diseno de farmacos, Seccion de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Díaz Miron S/N, Col, Casco de Santo Tomas, Mexico City, 11340 MX, Laboratorio de Modelado Molecular, Bioinformatica y diseno de farmacos, Seccion de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Díaz Miron S/N, Col, Casco de Santo Tomas, Mexico City, 11340 MX, Laboratorio de Modelado Molecular, Bioinformatica y diseno de farmacos, Seccion de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Díaz Miron S/N, Col, Casco de Santo Tomas, Mexico City, 11340 MX, Laboratorio de Modelado Molecular, Bioinformatica y diseno de farmacos, Seccion de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Díaz Miron S/N, Col, Casco de Santo Tomas, Mexico City, 11340 MX, Instituto Nacional de Cancerologia, Mexico, DF, 14080, Escuela Nacional de Ciencias Biologicas, Departamento de Quimica Organica Prolongacion de Carpio y Plan de Ayala s/n, Miguel Hidalgo, Santo Tomas, Mexico DF, 11340, Laboratorio de Biofisica y Biocatalisis, Seccion de Estudios de Posgrado eInvestigacion, Escuela Superior de Medicina Instituto Politecnico Nacional, Mexico City, 11340 MX, Laboratorio de Respiracion Celular, Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico City, 11340 MX, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Departamento de Biologia de la Reproduccion, Tlalpan, DF, 14000 MX, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Departamento de Biologia de la Reproduccion, Tlalpan, DF, 14000 MX, Laboratorio de Modelado Molecular, Bioinformatica y diseno de farmacos, Seccion de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Díaz Miron S/N, Col, Casco de Santo Tomas, Mexico City, 11340 MX, Laboratorio de Modelado Molecular, Bioinformatica y diseno de farmacos, Seccion de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Díaz Miron S/N, Col, Casco de Santo Tomas, Mexico City, 11340 MX
Keywords:Estrogen receptor, affinity, breast cancer, docking analysis, analogues, anti-proliferative.
Abstract:Estrogen (17β-estradiol) is essential for normal growth and differentiation in the mammary gland. In the last
three decades, previous investigations have revealed that Estrogen Receptor Alpha (ERα) plays a critical role in breast
cancer. More recently, observations regarding the widespread expression of ERβ-like proteins in normal and neoplastic
mammary tissues have suggested that ERβ is also involved in the mentioned pathology. Design of new drugs both steroidal
and nonsteroidal that target any of these receptors represents a promise to treat breast cancer although it remains a
challenge due to the sequence similarity between their catalytic domains.
In this work, we propose a new set of compounds that could effectively target the estrogen receptors ERα and ERβ.
These ligands were designed based on the chemical structure of the ERβ-selective agonist Diarylpropionitrile (DPN).
The designed ligands were submitted to in silico ADMET studies, yielding in a filtered list of ligands that showed better
drug-like properties. Molecular dynamics simulations of both estrogen receptors and docking analysis were carried-out
employing the designed compounds, from which two were chosen due to their promising characteristics retrieved from
theoretical results (docking analysis or targeting receptor predictions). They were chemically synthetized and during the
process, two precursor ligands were also obtained.
These four ligands were subjected to biological studies from which it could be detected that compound mol60b
dislplayed inhibitory activity and its ability to activate the transcription via an estrogenic mechanism of action was also
determined. Interestinly, this observation can be related to theoretical binding free energy calculations, where the
complex: ERβ-mol60b showed the highest energy ΔGbind value in comparison to others.
