Estrogen-receptor ligands

The three-dimensional structure of the ER was resolved by Brzozowski et al. [61]. Four additional X-ray structures of the receptor liganded with different molecules - estradiol, diethylstilbestrol, a nonsteroidal stilben derivative, and two antagonists raloxifen and 4-hydroxytamoxifen - were also solved [61, 62]. The availability of several structurally diverse structures bound to the active site of the receptor provided important experimental information detailing the molecular alignment of the studied molecules. 

To further validate the results obtained by the automated docking procedure, the receptor binding pocket was analyzed using program GRID [41]. The hydroxy. 

The comparison of the GRID/GOLPE results with a ligand-based CoMFA model, (q loo value of 0.796) [60], indicated that the ligand alignment constructed on the basis of the receptor structure supplies a better explanation of the biological activities. This is also indicated by smaller deviations of the calculated from the experimental values in the receptor-based model [35]. 

To further validate the GRID/GOLPE model it was necessary to test its predictiv-ity for external test sets. We carefully checked the literature for further ER data sets, which were experimentally tested in the same assay under the same conditions [67-70], In order to test the general predictivity 36 structurally diverse ER ligands were selected from the mentioned studies (examples are shown in Fig. 7.3, the whole data set is described in detail in [36]). 

All test set ligands were docked and scored as described in the methods section. For three compounds Auto Dock was not able to find any low energy conformation. A visual inspection of the binding site revealed that these compounds can only bind in a low energy conformation if several amino acids change their side-chain orientation. In the present version of AutoDock receptor flexibility cannot be considered. The remaining compounds were successfully docked by the Auto- 

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Gao H, Williams C, Labute P, Bajorath J. Binary quantitative structure-activity relationship (QSAR) analysis of estrogen receptor ligands. / Chem Inf Comput Sci 1999 39 164-8. 

SiPPL, W. Receptor-based 3D QSAR analysis of estrogen receptor ligands — merging the accuracy of... 

Sippl, W. Receptor-based 3D Quantitative Structure-Activity Relationships of Estrogen Receptor Ligands./. Comput.-Aided. Mol. Des., 2000, 14, 559-572. 

Feil, R., Wagner, J., Metzger, D., and Chambon, P. (1997) Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochem. Biophys. Res. Commun. 237, 752-757. 

Sadler, B.R., Cho, S.J., Ishaq, K.S., Chae, K., and Korach, K.S., Three-dimensional quantitative structure-activity relationship study of nonsteroidal estrogen receptor ligands using the comparative molecular field analysis cross-validated r2-guided region selection approach, J. Med. Chem., 41, 2261-2267, 1998. 

Kym, P. R. Anstead, G. M. Pinney, K. G. Wilson, S. R. Katzenellenbogen, J. A. Molecular structures, conformational analysis, and preferential modes of binding of 3-aroyl-2-arylbenzo[b]thiophene estrogen receptor ligands LYl 17018 and aryl azide photoaffinity labeling analogs, J. Med. Chem. 1993, 36, 3910-3922. 

A synthetic route to Q, /i-disubstituted cycloalkenones via a four step one-pot synthesis employed (4a) for RCM and then oxidative rearrangement giving products in low to moderate overall yields as a way to access estrogen receptor ligand tetrahydrofluorenones (equation 29)3 Crimmins reported an asymmetric aldol-oleftn metathesis approach to the synthesis of functionalized cyclopentenes exploiting the acyclic stereocontrol of the aldol reaction with efficient (2a) catalyzed RCM (equation 30)3 ... 

Sippl, W. Binding Affinity Prediction of Novel Estrogen Receptor Ligands Using... 

Wurtz, J. M., Egner, U., Heinrich. N., Moras, D., Mueller-Fahrnow, A. Three-Dimensional Models of Estrogen Receptor Ligand Binding Domain Complexes, Based on Related Crystal Structures and Mutational and Structure-Activity Relationships Data,/. Med. Chem. 1998, 41, 1803-1814. 

K., Korach, K.S. Three-Dimensional Structure-Activity Relationship Study of Nonsteroidal Estrogen Receptor Ligands Using the Comparative Molecular Field Analysis/Cross-Validated r -Guided Region Selection Approach,/. Med. Chem. 1998, 41, 2261-2267. 

Gao, H., Williams, C, Labute, P. and Bajorath, J. (1999). Binary Quantitative Structure-Activity Relationship (QSAR) Analysis of Estrogen Receptor Ligands. J.Chem.lnf.Comput.Sci., 39, 164-168. 

Bradbury S, Kamenska V, Schmieder PK, Ankley G, Mekenyan O. A computationally based identification algorithm for estrogen receptor ligands Part 1. Predicting hERalpha binding affinity. Toxicol Sci 2000 58 253-69. 

Sippl W. Binding affinity prediction of novel estrogen receptor ligands using receptor-based 3-D QSAR methods. Bioorg Med Chem 2002 10 3741-55. 

Stauffer SR, Sun J, Katzenellenbogen BS, Katzenellenbogen JA. Acyclic amides as estrogen receptor ligands synthesis, binding, activity and receptor interaction. Bioorg Med Chem 2000 8 1293-316. 

McDevitt RE, Malamas MS, Manas ES, Unwalla RJ, Xu ZB, Miller CP, Harris HA. Estrogen receptor ligands Design and synthesis of new 2-arylindene-l-ones. Bioorg Med Chem Lett 2005 15 3137-42. 

Sippl, W. Receptor-based 3D QSAR analysis of estrogen receptor ligands-merging the accuracy of receptor-based alignments with the computational efficiency of hgand-based methods. J. Comput-Aided Mol. Des. 2000,14,559-572. 

Klopman, G. and Chakravarti, S.K. (2003) Structure-activity relationship study of a diverse set of estrogen receptor ligands (1) using MultiCASE expert system. Chemosphere, 51, 445 59. 

Five of the 11 sets of inhibitors described in Section 6.4 were used again in the second scenario, namely the thrombin, gelatinase A, HIV protease, HIV reverse transcriptase, and COX2 data sets. A set of 29 p38 MAP kinase inhibitors was assembled from PDB crystal structures and Ref. [100]. A set of 40 estrogen receptor ligands was taken from the Protherics web site [101]. These two data sets were converted to Sybyl mol2 format and protonation states were adjusted as described above. 

McDormell, D.P. (1997) Dissection of the molecular mechanism of action of GW5638, a novel estrogen receptor ligand, provides insights into the role of estrogen receptor in bone. Endocrinology, 138, 3901-3911. 

Adelman, S.J., Steffan, R.J. and Harnish, D.C. (2005) Identification of pathway-selective estrogen receptor ligands that inhibit NF-kB transcriptional activity. Proceedings of the National Academy of Sciences of the United States of America, 102, 2543-2548. 

DaSilva, C.A., Pai, L.Y. et al. (2007) Estrogen receptor ligands. Part 16 2-aryl indoles as highly subtype selective ligands for ERa. Bioorganic el Medicinal Chemistry Letters, 17, 2322-2328. 

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