Molecular simulation of interaction between estrogen receptor and selective estrogen receptor modulators.
OBJECTIVE
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 conformationally 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.


CONCLUSIONS
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.
Guo
Zong-Ru
ZR
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. zrguo@imm.ac.cn
Yi
Xiang
X
Xu
Zhi-Bin
ZB
D001665:Binding Sites; D004958:Estradiol / Q000737:chemistry; D008024:Ligands; D018716:Molecular Mimicry; D020849:Raloxifene Hydrochloride / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry / Q000494:pharmacology*
D008024:Ligands; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D004958:Estradiol