In this manuscript, the procedure of molecular dynamics simulated annealing is applied to locate a probable receptor and binding site of a cyclicpeptide that inhibits
estrogen-stimulated proliferation of
breast cancer. The hydrophilic
cyclopeptide EMTOVNOGQ (O =
4-hydroxyproline), derived from
alpha-fetoprotein, is an inhibitor of
estrogen-stimulated proliferation of human
breast cancer. This
peptide has been shown to act through a mechanism different from that of
estrogen; however, its receptor is unknown. We report computer experiments that suggest that this
peptide may execute its actions by interacting with GPR30, a
G-protein-coupled receptor. The subject of this work is the simulation, by molecular dynamics simulated annealing, of the interaction of
cyclopeptide EMTOVNOGQ with receptor GPR30
protein. A conformational analysis of the
cyclopeptide was undertaken and the final structure was docked on several sites of the GPR30 3D model. Our results show that the
cyclopeptide interacts on the pocket located between TM6 and TM7 transmembrane helices of the
G-protein, triggering a slight conformational change in the secondary structure of the receptor in the complex. Based on differences in accessible surface areas between GPR30 and its
ligand, the residues in the interaction zone were identified. The
cyclopeptide is stabilized in the active site by forming a network of hydrogen bonds between Glu, Thr, (1)Pro(
OH) and GLn residues of the
ligand and Arg-259, Cys-271, Asn-316, Asn-320 and Tyr-324 of the
G-protein. Moreover, the study of the electrostatic surface potential on the GPR30 receptor shows that the active site is more positively charged than the other sites. Our modeling indicates a plausible interaction of the
cyclopeptide with the seven transmembrane GPR30
protein. This may have profound implications for the treatment of
breast cancer.