2-Hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic Acid
Current Medicinal Chemistry, 2012 Vol. 19, No. 4
623
[17]
Li, H.; Linton, A.; Tatlock, J.; Gonzalez, J.; Borchardt, A.; Abreo, M.;
Jewell, T.; Patel, L.; Drowns, M.; Ludlum, S.; Goble, M.; Yang, M.; Blazel,
J.; Rahavendran, R.; Skor, H.; Shi, S.; Lewis, C.; Fuhrman, S.A. Allosteric
with magnesium ions. Docking simulation was performed using the
GOLD 3.1 program on a Silicon Graphics Octane workstation with
dual 270 MHz MIPS R12000 processors. For each of the 50
independent GA runs, a maximum number of 100000 GA
inhibitors of hepatitis
C polymerase: discovery of potent and orally
bioavailable carbon-linked dihydropyrones. J. Med. Chem., 2007, 50, 3969-
3972.
operations were performed on
a single population of 100
[18]
[19]
Powers, J.P.; Piper, D.E.; Li, Y.; Mayorga, V; Anzola, J.; Chen, J.M.; Jaen,
J.C.; Lee, G.; Liu, J.; Peterson, M.G.; Tonn, G.R.; Ye, Q.; Walker, N.P.C.;
Wang, Z. SAR and mode of action of novel non-nucleoside inhibitors of
hepatitis C NS5b RNA polymerase. J. Med. Chem., 2006, 49, 1034-1046.
Gopalsamy, A.; Chopra, R.; Lim, K.; Ciszewski, G.; Shi, M.; Curran, K.J.;
Sukits, S.F.; Svenson, K.; Bard, J; Ellingboe, J.W.; Agarwal, A.;
Krishnamurthy, G.; Howe, A.Y.M.; Orlowski, M.; Feld, B.; O’Connell, J.;
Mansour, T.S. Discovery of proline sulfonamides as potent and selective
hepatitis C virus NS5b polymerase inhibitors. Evidence for a new NS5b
polymerase binding site. J. Med. Chem., 2006, 49, 3052-3055.
individuals. Operator weights for crossover, mutation, and
migration were set to 95, 95, and 10, respectively. The annealing
parameters for hydrogen bonding and van der Waals were set to 4.0
Å and 2.5 Å, respectively. The GoldScore fitness function was
applied for scoring. The docking region was defined to encompass
the UTP-binding site in the HCV NS5B crystal structure. The best
docking solution (with the highest GOLD fitness score) for
compound 11c was chosen to represent the predicted binding mode
to HCV NS5B.
[20]
[21]
[22]
Harper, S.; Avolio, S.; Pacini, B.; Di Filippo, M.; Altamura, S.; Tomei, L.;
Paonessa, G.; Di Marco, S.; Carfi, A.; Giuliano, C.; Padron, J.; Bonelli, F.;
Migliaccio, G.; De Francesco, R.; Laufer, R.; Rowley, M.; Narjes, F. Potent
inhibitors of subgenomic hepatitis
C virus RNA replication through
ACKNOWLEDGEMENTS
optimization of indole-N-acetamide allosteric inhibitors of the viral NS5B
polymerase. J. Med. Chem., 2005, 48, 4547-4557.
We thank Apath L.L.C. (St. Louis, MO) for the agreement to
use HCV replicon Ava.5 cells. This work was supported by
National Taiwan University (99R51101).
Pfefferkorn, J.A.; Greene, M.L.; Nugent, R.A.; Gross, R.J.; Mitchell, M.A.;
Finzel, B.C.; Harris, M.S.; Wells, P.A.; Shelly, J.A.; Anstadt, R.A.;
Kilkuskie, R.E.; Kopta, L.A.; Schwende, F.J. Inhibitors of HCV NS5b
polymerase. Part 1: evaluation of the southern region of (2Z)-2-
(benzoylamino)-3-(5-phenyl-2-furyl)acrylic acid. Bioorg. Med. Chem. Lett.,
2005, 15, 2481-2486.
Nittoli, T.; Curran, K.; Insaf, S.; DiGrandi, M.; Orlowski, M.; Chopra, R.;
Agarwal, A.; Howe, A.Y.M.; Prashad, A.; Floyd, M.B.; Johnson, B.;
Sutherland, A.; Wheless, K.; Feld, B.; O’Connell, J.; Mansour, T.S.; Bloom,
J. Identification of anthranilic acid derivatives as a novel class of allosteric
inhibitors of hepatitis C NS5B polymerase. J. Med. Chem., 2007, 50, 2108-
2116.
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers Web site
along with the published article.
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