Homology Models of the Human Androgen Receptor
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1739
(6) Brzozowski, A. M.; Pike, A. C.; Dauter, Z.; Hubbard, R. E.; Bonn,
T.; Engstrom, O.; Ohman, L.; Greene, G. L.; Gustafsson, J . A.;
Carlquist, M. Molecular basis of agonism and antagonism in the
oestrogen receptor. Nature 1997, 389, 753-8.
(7) Tanenbaum, D. M.; Wang, Y.; Williams, S. P.; Sigler, P. B.
Crystallographic comparison of the estrogen and progesterone
receptor’s ligand binding domains. Proc. Natl. Acad. Sci. U.S.A.
1998, 95, 5998-6003.
(8) Williams, S. P.; Sigler, P. B. Atomic structure of progesterone
complexed with its receptor. Nature 1998, 393, 392-6.
(9) Nolte, R. T.; Wisely, G. B.; Westin, S.; Cobb, J . E.; Lambert, M.
H.; Kurokawa, R.; Rosenfeld, M. G.; Willson, T. M.; Glass, C.
K.; Milburn, M. V. Ligand binding and co-activator assembly of
the peroxisome proliferator-activated receptor-gamma. Nature
1998, 395, 137-43.
(10) Xu, H. E.; Lambert, M. H.; Montana, V. G.; Parks, D. J .;
Blanchard, S. G.; Brown, P. J .; Sternbach, D. D.; Lehmann, J .
M.; Wisely, G. B.; Willson, T. M.; Kliewer, S. A.; Milburn, M. V.
Molecular recognition of fatty acids by peroxisome proliferator-
activated receptors. Mol. Cell 1999, 3, 397-403.
(29) Ris-Stalpers, C.; Hoogenboezem, T.; Sleddens, H. F.; Verleun-
Mooijman, M. C.; Degenhart, H. J .; Drop, S. L.; Halley, D. J .;
Oosterwijk, J . C.; Hodgins, M. B.; Trapman, J .; et al. A practical
approach to the detection of androgen receptor gene mutations
and pedigree analysis in families with x-linked androgen
insensitivity. Pediatr. Res. 1994, 36, 227-34.
(30) Nakao, R.; Haji, M.; Yanase, T.; Ogo, A.; Takayanagi, R.;
Katsube, T.; Fukumaki, Y.; Nawata, H. A single amino acid
substitution (Met786_Val) in the steroid-binding domain of
human androgen receptor leads to complete androgen insensitiv-
ity syndrome. J . Clin. Endocrinol. Metab. 1992, 74, 1152-7.
(31) Veldscholte, J .; Ris-Stalpers, C.; Kuiper, G. G.; J enster, G.;
Berrevoets, C.; Claassen, E.; van Rooij, H. C.; Trapman, J .;
Brinkmann, A. O.; Mulder, E. A mutation in the ligand binding
domain of the androgen receptor of human LNCaP cells affects
steroid binding characteristics and response to anti-androgens.
Biochem. Biophys. Res. Commun. 1990, 173, 534-40.
(32) De Bellis, A.; Quigley, C. A.; Marschke, K. B.; el-Awady, M. K.;
Lane, M. V.; Smith, E. P.; Sar, M.; Wilson, E. M.; French, F. S.
Characterization of mutant androgen receptors causing partial
androgen insensitivity syndrome. J . Clin. Endocrinol. Metab.
1994, 78, 513-22.
(11) Rochel, N.; Wurtz, J . M.; Mitschler, A.; Klaholz, B.; Moras, D.
The crystal structure of the nuclear receptor for vitamin D bound
to its natural ligand. Mol. Cell 2000, 5, 173-9.
(33) Lundberg Giwercman, Y.; Nikoshkov, A.; Lindsten, K.; Bystrom,
B.; Pousette, A.; Chibalin, A. V.; Arvidsson, S.; Tiulpakov, A.;
Semitcheva, T. V.; Peterkova, V.; Hagenfeldt, K.; Ritzen, E. M.;
Wedell, A. Functional characterisation of mutations in the
ligand-binding domain of the androgen receptor gene in patients
with androgen insensitivity syndrome. Hum. Genet. 1998, 103,
529-31.
(34) Letz, M.; Bringmann, P.; Mann, M.; Mueller-Fahrnow, A.;
Reipert, D.; Scholz, P.; Wurtz, J . M.; Egner, U. Investigation of
the binding interactions of progesterone using muteins of the
human progesterone receptor ligand binding domain designed
on the basis of a three-dimensional protein model. Biochim.
Biophys. Acta 1999, 1429, 391-400.
(35) Poujol, N.; Wurtz, J . M.; Tahiri, B.; Lumbroso, S.; Nicolas, J .
C.; Moras, D.; Sultan, C. Specific recognition of androgens by
their nuclear receptor: a structure-function study. J . Biol.
Chem. 2000, 275, 24022-24031.
(36) Kirkovsky, L.; Mukherjee, A.; Yin, D.; Dalton, J . T.; Miller, D.
D. Chiral nonsteroidal affinity ligands for the androgen receptor.
1. Bicalutamide analogues bearing electrophilic groups in the
B aromatic ring. J . Med. Chem. 2000, 43, 581-90.
(37) Case, D. A.; Pearlman, D. A.; Cladwell, J . W.; Cheatham, T. E.,
III; Ross, W. S.; Simmerling, C. L.; Darden, T. A.; Merz, K. M.;
Stanton, R. V.; Cheng, A. L.; Vincent, J . J .; Crowley, M.;
Ferguson, D. M.; Radmer, R. J .; Seibel, G. L.; Singh, U. C.;
Weiner, P. K.; Kollman, P. A. AMBER 5; University of Califor-
nia: San Francisco, 1997.
(38) Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz J r.,
K. M.; Ferguson, D. M.; Spellmeyer, D. C.; Fox, T.; Caldwell, J .
W.; Kollman, P. A. A Second Generation Force Field for the
Simulation of Proteins, Nucleic Acids, and Organic Molecules.
J . Am. Chem. Soc. 1995, 117, 5179-5197.
(39) Bayly, C. I.; Cieplak, P.; Cornell, W. D.; Kollman, P. A. A Well-
Behaved Electrostatic Potential Based Method Using Charge
Restraints For Determining Atom-Centered Charges: The RESP
Model. J . Phys. Chem. 1993, 97, 10269-10280.
(40) Cieplak, P.; Cornell, W. D.; Bayly, C.; Kollman, P. A. Applications
of the Multimolecule and Multiconformational RESP Methodol-
ogy to Biopolymers: Charge Derivation for DNA, RNA, and
Proteins. J . Comput. Chem. 1995, 16, 1357-1377.
(41) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery,
J . A.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J .
M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.;
Tomasi, J .; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.;
Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J .; Petersson, G.
A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck,
A. D.; Raghavachari, K.; Foresman, J . B.; Cioslowski, J .; Ortiz,
J . V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.;
Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen, W.; Wong,
M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.; Pople,
J . A. Gaussian 98 (Revision A.9); Gaussian, Inc: Pittsburgh, PA,
1998.
(42) Wang, J .; Cieplak, P.; Kollman, P. A. How well does a restrained
electrostatic potential (RESP) model perform in calculating
conformational energies of organic and biological molecules? J .
Comput. Chem. 2000, 21, 1049-1074.
(43) Labaree, D. C.; Hoyte, R. M.; Nazareth, L. V.; Weigel, N. L.;
Hochberg, R. B. 7alpha-Iodo and 7alpha-fluoro steroids as
androgen receptor-mediated imaging agents. J . Med. Chem.
1999, 42, 2021-34.
(12) Matias, P. M.; Donner, P.; Coelho, R.; Thomaz, M.; Peixoto, C.;
Macedo, S.; Otto, N.; J oschko, S.; Scholz, P.; Wegg, A.; Basler,
S.; Schafer, M.; Ruff, M.; Egner, U.; Carrondo, M. A. Structural
evidence for ligand specificity in the binding domain of the
human Androgen receptor: implications for pathogenic gene
mutations. J . Biol. Chem. 2000, 275, 26164-26171.
(13) Furr, B. J . A.; Tucker, H. The Preclinical Development of
Bicalutamide: Pharmacodynamics and Mechanism of Action.
Urology 1996, 47, 13-25.
(14) Morris, J . J .; Hughes, L. R.; Glen, A. T.; Taylor, P. J . Nonste-
roidal antiandrogens. Design of novel compounds based on an
infrared study of the dominant conformation and hydrogen-
bonding properties of a series of anilide antiandrogens. J . Med.
Chem. 1991, 34, 447-55.
(15) Mukherjee, A.; Kirkovsky, L.; Yao, X. T.; Yates, R. C.; Miller,
D. D.; Dalton, J . T. Enantioselective binding of Casodex to the
androgen receptor. Xenobiotica 1996, 26, 117-22.
(16) Caves, L. S.; Evanseck, J . D.; Karplus, M. Locally accessible
conformations of proteins: multiple molecular dynamics simula-
tions of crambin. Protein Sci. 1998, 7, 649-66.
(17) Colombo, G.; Merz, K. M., J r. Stability and Activity of Mesophilic
Subtilisin
E and Its Thermophilic Homolog: Insights from
Molecular Dynamics Simulations. J . Am. Chem. Soc. 1999, 121,
6895-6903.
(18) York, D. M.; Darden, T. A.; Pedersen, L. G.; Anderson, M. W.
Molecular dynamics simulation of HIV-1 protease in a crystalline
environment and in solution. Biochemistry 1993, 32, 1443-53.
(19) Langley, E.; Kemppainen, J . A.; Wilson, E. M. Intermolecular
NH2-/carboxyl-terminal interactions in androgen receptor dimer-
ization revealed by mutations that cause androgen insensitivity.
J . Biol. Chem. 1998, 273, 92-101.
(20) Singh, S. M.; Gauthier, S.; Labrie, F. Androgen receptor an-
tagonists (antiandrogens): structure-activity relationships.
Curr. Med. Chem. 2000, 7, 211-47.
(21) Ferrin, T. E.; Huang, C. C.; J arvis, L. E.; Langridge, R. The
MIDAS display system. J . Mol. Graphics 1988, 6, 13-27.
(22) Huang, C. C.; Pettersen, E. F.; Klein, T. E.; Ferrin, T. E.;
Langridge, R. CONIC: A fast renderer for space-filling molecules
with shadows. J . Mol. Graphics 1991, 9, 230-236.
(23) Laskowski, R. A.; MacArthur, M. W.; Moss, D. S.; Thornton, J .
M. PROCHECK: a program to check the stereochemical quality
of protein structures. J . Appl. Crystallogr. 1993, 26, 283-291.
(24) De Bellis, A.; Quigley, C. A.; Cariello, N. F.; el-Awady, M. K.;
Sar, M.; Lane, M. V.; Wilson, E. M.; French, F. S. Single base
mutations in the human androgen receptor gene causing com-
plete androgen insensitivity: rapid detection by a modified
denaturing gradient gel electrophoresis technique. Mol. Endo-
crinol. 1992, 6, 1909-20.
(25) Lumbroso, S.; Lobaccaro, J . M.; Georget, V.; Leger, J .; Poujol,
N.; Terouanne, B.; Evain-Brion, D.; Czernichow, P.; Sultan, C.
A novel substitution (Leu707Arg) in exon 4 of the androgen
receptor gene causes complete androgen resistance. J . Clin.
Endocrinol. Metab. 1996, 81, 1984-8.
(26) Marcelli, M.; Zoppi, S.; Wilson, C. M.; Griffin, J . E.; McPhaul,
M. J . Amino acid substitutions in the hormone-binding domain
of the human androgen receptor alter the stability of the
hormone receptor complex. J . Clin. Invest. 1994, 94, 1642-50.
(27) Bevan, C. L.; Brown, B. B.; Davies, H. R.; Evans, B. A.; Hughes,
I. A.; Patterson, M. N. Functional analysis of six androgen
receptor mutations identified in patients with partial androgen
insensitivity syndrome. Hum Mol Genet 1996, 5, 265-73.
(28) Batch, J . A.; Williams, D. M.; Davies, H. R.; Brown, B. D.; Evans,
B. A.; Hughes, I. A.; Patterson, M. N. Androgen receptor gene
mutations identified by SSCP in fourteen subjects with androgen
insensitivity syndrome. Hum. Mol. Genet. 1992, 1, 497-503.