Molecular mapping of heterocyclic diazene derivatives for estrogen receptor modulation.
Indian J Biochem Biophys
;
2012 Aug; 49(4): 236-245
Artículo
en Inglés
| IMSEAR
| ID: sea-140241
ABSTRACT
Selective estrogen receptor modulators (SERMs) are effectively used in hormone replacement therapy (HRT) by reducing post-menopausal symptoms, including hormone-responsive breast cancer and osteoporosis. The present study explored the pharmacophore features of diazene derivatives for selective estrogen receptor (ER) modulation using quantitative structure activity relationship (QSAR) and space modeling approaches. The 2D-QSAR models (R2α = 0.907, Q2α = 0.700, R2pred-α = 0.735; R2β = 0.913, Q2β = 0.756, R2pred-β = 0.745) showed the importance of orbital energies, hydrophobicity, refractivity and atomic charges for selective binding affinity to ER. In 3D-QSAR, molecular field (CoMFA, R2α = 0.948, Q2 = 0.720, R2pred-α = 0.708; R2β = 0.994, Q2β = 0.541, R2pred-β = 0.721) and similarity models (CoMSIA, R2α = 0.984, Q2α = 0.793, R2pred-α = 0.738; R2β = 0.996, Q2β = 0.681, R2pred-β = 0.725) indicated that steric and hydrophobic properties were important for binding selectivity. Space modeling study (R2α = 0.885, Q2α = 0.855, R2pred-α = 0.666; R2β = 0.872, Q2β = 0.883, R2pred-β = 0.814) revealed that hydrophobic and aromatic ring features were important for both subtypes, whereas hydrogen bond (HB) acceptor and donor were crucial for β- and α-subtypes, respectively. Interactions observed between ligand and catalytic residues at the active site in docking study substantiated the developed model which may be successfully used in high throughput screening (HTS) to obtain promising lead molecules for selective estrogen therapy.
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Asunto principal:
Modelos Moleculares
/
Receptores de Estrógenos
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Moduladores Selectivos de los Receptores de Estrógeno
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Proteínas de Unión al ADN
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Simulación del Acoplamiento Molecular
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Compuestos Heterocíclicos
Idioma:
Inglés
Revista:
Indian J Biochem Biophys
Año:
2012
Tipo del documento:
Artículo
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