雌激素受体和选择性雌激素受体调节剂相互作用的分子模拟

目的:研究一类高活性消旋化的雌激素受体调节剂与其受体间的相互作用机制.方法:分子力学优化的方法获得这类刚性的raloxifene类似物的活性构象,受体与配基间的相互作用能用分子对接程序计算.结果:化合物的R和S构型均可进入雌激素受体的结合腔.其羟基直接与受体氨基酸形成氢键,其酚环相当于雌激素的A环.活性最好的配基带有两个羟基,并已模拟雌激素A环为含16位羟基的酚环的S构型化合物.结论:消旋化对该类化合物的活性影响不大.羟基对于化合物在活性11袋中的取向及与受体的结合有着重要意义.

Molecular simulation of interaction between estrogen receptor and selective estrogen receptor modulators

To study the mechanism of interaction between a series of potent racemic selective estrogen receptor modulators ( SERM ) and estrogen receptors ( ER). METHODS: Active conformations of these conforma-tionally restricted raloxifene analogues in binding pocket were determined by molecular mechanics. The interactive energies between ligand and receptor were calculated by docking program. RESULTS: Both R and S configurations of these SERM were accommodated by the binding pocket of ER. The hydroxy group of compounds forms hydrogen bonds with amino acid residues of ER and the phenolic group mimics the A-ring of estradiol. The most potential compounds were those with two hydroxy groups and accommodated by binding pocket in S configuration with phenolic group at C (16) imitating A-ring of estradiol. CONCLUSION: Chiral center conferred little effect on the binding affinity of these conformationally restricted raloxifene analogues. The hydroxy group (s) play (s) a critical role to the orientation of compounds in active pocket of ER and the binding between ligand and receptor.