Alvarez Lautaro D, Martí Marcelo A, Veleiro Adriana S, Misico Rosana I, Estrin Darío A, Pecci Adalí, Burton Gerardo
Departamento de Química Orgánica and UMYMFOR-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, C1428EGA Buenos Aires, Argentina.
ChemMedChem. 2008 Dec;3(12):1869-77. doi: 10.1002/cmdc.200800256.
The introduction of a hemisuccinate group at the 21-position of the passive antiglucocorticoid 21OH-6,19OP leads to a compound (21HS-6,19OP) with a notable activity profile toward the glucocorticoid receptor (GR). In contrast to the parent steroid, 21HS-6,19OP behaves as a pure agonist of GR activity in direct transactivation assays. However, the apoptotic effects of 21HS-6,19OP show that the effect depends on cell type: while 21HS-6,19OP is a pure agonist in L929 mouse fibroblasts, in thymocytes 21HS-6,19OP had significant antiglucocorticoid activity. This tissue-specific activity makes 21HS-6,19OP a novel selective GR modulator. To investigate the molecular basis of action of 21HS-6,19OP, we carried out molecular dynamics simulations (6 ns) of the GR ligand binding domain (LBD) complexed with 21HS-6,19OP. Our results indicate that the hemisuccinate moiety may play a key role in stabilizing the active conformation of the receptor dimerization interface, reverting the changes observed with the antagonist 21OH-6,19OP. Other changes in regions of the GR related to cofactor recruitment (possibly tissue-specific), could explain this particular activity profile.
在被动抗糖皮质激素21OH - 6,19OP的21位引入半琥珀酸基团，可得到一种对糖皮质激素受体（GR）具有显著活性特征的化合物（21HS - 6,19OP）。与母体类固醇不同，在直接反式激活试验中，21HS - 6,19OP表现为GR活性的纯激动剂。然而，21HS - 6,19OP的凋亡作用表明，其作用取决于细胞类型：在L929小鼠成纤维细胞中，21HS - 6,19OP是一种纯激动剂，而在胸腺细胞中，21HS - 6,19OP具有显著的抗糖皮质激素活性。这种组织特异性活性使21HS - 6,19OP成为一种新型的选择性GR调节剂。为了研究21HS - 6,19OP的作用分子基础，我们对与21HS - 6,19OP复合的GR配体结合域（LBD）进行了分子动力学模拟（6纳秒）。我们的结果表明，半琥珀酸部分可能在稳定受体二聚化界面的活性构象中起关键作用，逆转了拮抗剂21OH - 6,19OP所观察到的变化。GR中与辅因子募集相关区域的其他变化（可能具有组织特异性），可以解释这种特殊的活性特征。
