A. Huang et al. / Bioorg. Med. Chem. 15 (2007) 6170–6181
6181
15. (a) Levin, J. I.; Venkatesan, A. M.; Chen, J. M.; Zask, A.;
Sandanayaka, V. P.; Du, M. T.; Baker, J. L. U.S. 6358980,
2002; (b) Huang, A.; Condon, J.; Joseph-McCarthy, D.;
Lombart, H.; Lovering, F.; Park, K.; Rao, V.; Sun, L.;
Wang, Q.; Wang, W.; Xu, W.; Zeng, C.; Zhang, Y.; Zhu,
Z.; Levin, J. I. Poster, AAPS Conference: Critical Issues in
Discovering Quality Clinical Candidates, Philadelphia,
PA, April 24–26, 2006.
16. (a) Zask, A.; Kaplan, J.; Du, X.; MacEwan, G.; San-
danayaka, V.; Eudy, N.; Levin, J.; Jin, G.; Xu, J.;
Cummons, T.; Barone, D.; Ayral-Kaloustian, S.; Skotn-
icki, J. Bioorg. Med. Chem. Lett. 2005, 15, 1641; (b) Levin,
J. I.; Chen, J. M.; Laakso, L. M.; Du, M.; Du, X.;
Venkatesan, A. M.; Sandanayaka, V.; Zask, A.; Xu, J.;
Xu, W.; Zhang, Y.; Skotnicki, J. S. Bioorg. Med. Chem.
Lett. 2005, 15, 4345; (c) Tsukida, T.; Moriyama, H.;
Inoue, Y.; Kondo, H.; Yoshino, K.; Nishimura, S. Bioorg.
Med. Chem. Lett. 2004, 14, 1569; (d) Moriyama, H.;
Tsukida, T.; Inoue, Y.; Yokota, K.; Yoshino, K.; Kondo,
H.; Miura, N.; Nishimura, S.-I. J. Med. Chem. 2004, 47,
1930.
17. (a) Initial models for compounds 5 and 7 bound to TACE,
respectively, were generated via Monte Carlo docking
using the program FLO (McMartin, C.; Bohacek, R. S. J.
Comput.-Aided Mol. Design, 1997, 11, 333–344). A scan of
the linker dihedral (the dihedral about the O–CH2 bond)
was carried out starting with the modeled bound confor-
mation of compound 5 with TACE. A similar scan of the
linker dihedral (about the NH–CH2 bond) was carried out
starting with 7 in the identical conformation. For both
ligand structures, the quantum mechanical energy of
ligand was calculated while varying the linker dihedral in
5ꢂ increments from ꢀ180ꢂ to +180ꢂ. The program Jaguar
6.0 (Schro¨dinger, LLC, Portland, OR, 2005) was used to
perform a relaxed coordinate scan of the specified dihedral
angles at the B3LYP/6-31G** level of theory, including a
Poisson–Boltzmann self-consistent reaction field model to
account for the effects of aqueous solvation; (b) The RCSB
PDB ID code of the X-ray structure of 7 bound to MMP-
13 is 2PJT.
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