Discovery and structure-activity analysis of selective estrogen receptor modulators via similarity-based virtual screening.

A number of selective estrogen receptor modulators (SERMs) were discovered from the SPECS database via a simple protocol. Based on two reference SERMs we identified via structure-based virtual screening previously, ligand-based similarity search and molecular docking filtering were conducted to identify novel SERMs from SPECS library. Among the 36 purchased compounds, 21 were confirmed to be active by in vitro assays, and 10 showed dual profile properties, namely as antagonists of ERα and agonists of ERβ. The anti-proliferative potency of these ligands was also evaluated against MCF-7 cell lines. Further investigation of the anti-proliferative mechanism of compound 3a suggested that it induced a G1 cell cycle arrest in ERα positive MCF-7 cell through ERα mediated cyclin D1 down-regulation.

[1]  Tianlin Wang,et al.  Recent advances in selective estrogen receptor modulators for breast cancer. , 2009, Mini reviews in medicinal chemistry.

[2]  Emma Lees,et al.  Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice , 1994, Nature.

[3]  Weihua Li,et al.  Discovery of potent ligands for estrogen receptor beta by structure-based virtual screening. , 2010, Journal of medicinal chemistry.

[4]  K E Carlson,et al.  Estrogen receptor subtype-selective ligands: asymmetric synthesis and biological evaluation of cis- and trans-5,11-dialkyl- 5,6,11, 12-tetrahydrochrysenes. , 1999, Journal of medicinal chemistry.

[5]  Jin Huang,et al.  Butyl 4-(butyryloxy)benzoate functions as a new selective estrogen receptor β agonist and induces GLUT4 expression in CHO-K1 cells , 2008, The Journal of Steroid Biochemistry and Molecular Biology.

[6]  J. Gustafsson,et al.  Cloning of a novel receptor expressed in rat prostate and ovary. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Maria A Miteva,et al.  Structure-based virtual ligand screening: recent success stories. , 2009, Combinatorial chemistry & high throughput screening.

[8]  J. Gustafsson,et al.  Role of estrogen receptor beta in estrogen action. , 2001, Annual review of physiology.

[9]  Jiri Bartek,et al.  Cyclin D1 protein expression and function in human breast cancer , 1994, International journal of cancer.

[10]  G. Cheon,et al.  Synthesis and Evaluation of Estrogen Receptor β-Selective Ligands: Fluoroalkylated Indazole Estrogens , 2008 .

[11]  Eric S Manas,et al.  Structure-based design of estrogen receptor-beta selective ligands. , 2004, Journal of the American Chemical Society.

[12]  R. Bernards,et al.  CDK-Independent Activation of Estrogen Receptor by Cyclin D1 , 1997, Cell.

[13]  V. Jordan,et al.  Potential of selective estrogen receptor modulators as treatments and preventives of breast cancer. , 2009, Anti-cancer agents in medicinal chemistry.

[14]  Ettore Novellino,et al.  Pursuing aldose reductase inhibitors through in situ cross-docking and similarity-based virtual screening. , 2009, Journal of medicinal chemistry.

[15]  Willem Dhooge,et al.  Subtle Side-Chain Modifications of the Hop Phytoestrogen 8-Prenylnaringenin Result in Distinct Agonist/Antagonist Activity Profiles for Estrogen Receptors α and β , 2006 .

[16]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[17]  S. Safe,et al.  Estrogen Regulation of Cyclin D1 Gene Expression in ZR-75 Breast Cancer Cells Involves Multiple Enhancer Elements* , 2001, The Journal of Biological Chemistry.

[18]  Hualiang Jiang,et al.  Computational insights into the mechanism of ligand unbinding and selectivity of estrogen receptors. , 2009, The journal of physical chemistry. B.

[19]  J. Gustafsson,et al.  Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. , 1997, Endocrinology.

[20]  J. Pickar,et al.  SERMs: progress and future perspectives. , 2010, Maturitas.

[21]  Zbigniew Dauter,et al.  Molecular basis of agonism and antagonism in the oestrogen receptor , 1997, Nature.

[22]  Weihua Li,et al.  Insights into ligand selectivity in estrogen receptor isoforms: molecular dynamics simulations and binding free energy calculations. , 2008, The journal of physical chemistry. B.

[23]  Richard A. Friesner,et al.  What role do surfaces play in GB models? A new‐generation of surface‐generalized born model based on a novel gaussian surface for biomolecules , 2006, J. Comput. Chem..