4464 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14
Mpamhanga et al.
Structural Proteomics Facility (SSPF) for additional financial
support and Openeye for free software licenses. Further, we
thank Nicholas Moir for administrating the Linux work-
stations and Dr. Mark Agacan for maintenance of the in-
house X-ray crystallography facilities.
(14) Ecker, G. F.; Noe, C. R. In silico prediction models for blood-
brain barrier permeation. Curr. Med. Chem. 2004, 11, 1617–
1628.
(15) Dawson, A.; Gibellini, F.; Sienkiewicz, N.; Tulloch, L. B.; Fyfe, P.
K.; McLuskey, K.; Fairlamb, A. H.; Hunter, W. N. Structure and
reactivity of Trypanosoma brucei pteridine reductase: inhibition by
the archetypal antifolate methotrexate. Mol. Microbiol. 2006, 61,
1457–1468.
(16) Gourley, D. G.; Schuttelkopf, A. W.; Leonard, G. A.; Luba, J.;
Hardy, L. W.; Beverley, S. M.; Hunter, W. N. Pteridine reductase
mechanism correlates pterin metabolism with drug resistance in
trypanosomatid parasites. Nat. Struct. Biol. 2001, 8, 521–525.
(17) Congreve, M.; Chessari, G.; Tisi, D.; Woodhead, A. J. Recent
Developments in Fragment-Based Drug Discovery. J. Med. Chem.
2008, 51, 3661–3680.
Supporting Information Available: A table listing initial
screening hits with corresponding percent inhibition data is
available as Supporting Information.This material is available
References
(18) Hajduk, P. J.; Greer, J. A decade of fragment-based drug design:
strategic advances and lessons learned. Nat. Rev. Drug. Discovery
2007, 6, 211–219.
(1) Pink, R.; Hudson, A.; Mouries, M. A.; Bendig, M. Opportunities
and challenges in antiparasitic drug discovery. Nat. Rev. Drug.
Discovery 2005, 4, 727–740.
(19) Brenk, R.; Schipani, A.; James, D.; Krasowski, A.; Gilbert, I. H.;
Frearson, J.; Wyatt, P. G. Lessons learned from assembling screen-
ing libraries for drug discovery for neglected diseases. ChemMed-
Chem 2008, 3, 435–444.
(20) Lorber, D. M.; Shoichet, B. K. Flexible ligand docking using
conformational ensembles. Protein Sci. 1998, 7, 938–950.
(21) Wei, B. Q.; Baase, W. A.; Weaver, L. H.; Matthews, B. W.;
Shoichet, B. K. A model binding site for testing scoring functions
in molecular docking. J. Mol. Biol. 2002, 322, 339–355.
(22) Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: a useful
metric for lead selection. Drug Discovery Today 2004, 9, 430–
431.
(23) Schuttelkopf, A. W.; Hardy, L. W.; Beverley, S. M.; Hunter, W. N.
Structures of Leishmania major Pteridine Reductase Complexes
Reveal the Active Site Features Important for Ligand Binding
and to Guide Inhibitor Design. J. Mol. Biol. 2005, 352, 105–
116.
(24) Chen, H.; Lyne, P. D.; Giordanetto, F.; Lovell, T.; Li, J. On
evaluating molecular-docking methods for pose prediction and
enrichment factors. J. Chem. Inf. Model. 2006, 46, 401–415.
(25) McGaughey, G. B.; Sheridan, R. P.; Bayly, C. I.; Culberson, J. C.;
Kreatsoulas, C.; Lindsley, S.; Maiorov, V.; Truchon, J. F.; Cornell,
W. D. Comparison of Topological, Shape, and Docking Methods in
Virtual Screening. J. Chem. Inf. Model. 2007, 47, 1504–1519.
(26) Tan, L.; Geppert, H.; Sisay, M. T.; Gutschow, M.; Bajorath, J.
Integrating Structure- and Ligand-Based Virtual Screening: Com-
parison of Individual, Parallel, and Fused Molecular Docking and
Similarity Search Calculations on Multiple Targets. ChemMed-
Chem 2008, 3, 1566–1571.
(2) Brun, R.; Balmer, O. New developments in human African trypa-
nosomiasis. Curr. Opin. Infect. Dis. 2006, 19, 415–420.
(3) Kennedy, P. G. The continuing problem of human African
trypanosomiasis (sleeping sickness). Ann. Neurol. 2008, 64,
116–126.
(4) Nare, B.; Luba, J.; Hardy, L. W.; Beverley, S. New approaches to
Leishmania chemotherapy: pteridine reductase 1 (PTR1) as a target
and modulator of antifolate sensitivity. Parasitology 1997, 114
(Suppl.), S101–S110.
(5) Berriman, M.; Ghedin, E.; Hertz-Fowler, C.; Blandin, G.; Re-
nauld, H.; Bartholomeu, D. C.; Lennard, N. J.; Caler, E.; Hamlin,
N. E.; Haas, B.; Bohme, U.; Hannick, L.; Aslett, M. A.; Shallom, J.;
Marcello, L.; Hou, L.; Wickstead, B.; Alsmark, U. C.; Arrowsmith,
C.; Atkin, R. J.; Barron, A. J.; Bringaud, F.; Brooks, K.;
Carrington, M.; Cherevach, I.; Chillingworth, T. J.; Churcher,
C.; Clark, L. N.; Corton, C. H.; Cronin, A.; Davies, R. M.;
Doggett, J.; Djikeng, A.; Feldblyum, T.; Field, M. C.; Fraser, A.;
Goodhead, I.; Hance, Z.; Harper, D.; Harris, B. R.; Hauser, H.;
Hostetler, J.; Ivens, A.; Jagels, K.; Johnson, D.; Johnson, J.; Jones,
K.; Kerhornou, A. X.; Koo, H.; Larke, N.; Landfear, S.; Larkin,
C.; Leech, V.; Line, A.; Lord, A.; Macleod, A.; Mooney, P. J.;
Moule, S.; Martin, D. M.; Morgan, G. W.; Mungall, K.; Norbertc-
zak, H.; Ormond, D.; Pai, G.; Peacock, C. S.; Peterson, J.; Quail,
M. A.; Rabbinowitsch, E.; Rajandream, M. A.; Reitter, C.;
Salzberg, S. L.; Sanders, M.; Schobel, S.; Sharp, S.; Simmonds,
M.; Simpson, A. J.; Tallon, L.; Turner, C. M.; Tait, A.; Tivey, A.
R.; Van Aken, S.; Walker, D.; Wanless, D.; Wang, S.; White, B.;
White, O.; Whitehead, S.; Woodward, J.; Wortman, J.; Adams, M.
D.; Embley, T. M.; Gull, K.; Ullu, E.; Barry, J. D.; Fairlamb, A. H.;
Opperdoes, F.; Barrell, B. G.; Donelson, J. E.; Hall, N.; Fraser, C.
M.; Melville, S. E.; El-Sayed, N. M. The genome of the African
trypanosome Trypanosoma brucei. Science 2005, 309, 416–422.
(6) Gangjee, A.; Jain, H. D.; Kurup, S. Recent advances in classical
and non-classical antifolates as antitumor and antiopportunistic
infection agents: part I. Anticancer Agents Med. Chem. 2007, 7,
524–542.
(27) von Korff, M.; Freyss, J.; Sander, T. Comparison of Ligand- and
Structure-Based Virtual Screening on the DUD Data Set. J. Chem.
Inf. Model. 2009, 49, 209–231.
(28) Verdonk, M. L.; Berdini, V.; Hartshorn, M. J.; Mooij, W. T.;
Murray, C. W.; Taylor, R. D.; Watson, P. Virtual screening using
protein-ligand docking: avoiding artificial enrichment. J. Chem.
Inf. Comput. Sci. 2004, 44, 793–806.
(7) Gangjee, A.; Jain, H. D.; Kurup, S. Recent advances in classical
and nonclassical antifolates as antitumor and antiopportunistic
infection agents: Part II. Anticancer Agents Med. Chem. 2008, 8,
205–231.
(8) Bello, A. R.; Nare, B.; Freedman, D.; Hardy, L.; Beverley, S. M.
PTR1: a reductase mediating salvage of oxidized pteridines and
methotrexate resistance in the protozoan parasite Leishmania
major. Proc. Natl. Acad. Sci. 1994, 91, 11442–11446.
(9) Sienkiewicz, N.; Jaroslawski, S.; Wyllie, S.; Fairlamb, A. H. Chemical
and genetic validation of dihydrofolate reductase-thymidylate synthase
as a drug target in African trypanosomes. Mol. Microbiol. 2008, 69,
520–533.
(10) Nare, B.; Hardy, L. W.; Beverley, S. M. The roles of pteridine
reductase 1 and dihydrofolate reductase-thymidylate synthase in
pteridine metabolism in the protozoan parasite Leishmania major.
J. Biol. Chem. 1997, 272, 13883–13891.
(11) Cunningham, M. L.; Titus, R. G.; Turco, S. J.; Beverley, S. M.
Regulation of differentiation to the infective stage of the protozoan
parasite Leishmania major by tetrahydrobiopterin. Science 2001,
292, 285–287.
(12) Cavazzuti, A.; Paglietti, G.; Hunter, W. N.; Gamarro, F.; Piras, S.;
Loriga, M.; Allecca, S.; Corona, P.; McLuskey, K.; Tulloch, L.;
Gibellini, F.; Ferrari, S.; Costi, M. P. Discovery of potent pteridine
reductase inhibitors to guide antiparasite drug development. Proc.
Natl. Acad. Sci. 2008, 105, 1448–1453.
(29) Marcou, G.; Rognan, D. Optimizing fragment and scaffold dock-
ing by use of molecular interaction fingerprints. J. Chem. Inf.
Model. 2007, 47, 195–207.
(30) Mpamhanga, C. P.; Chen, B.; McLay, I. M.; Willett, P. Knowl-
edge-based interaction fingerprint scoring: a simple method for
improving the effectiveness of fast scoring functions. J. Chem. Inf.
Model. 2006, 46, 686–698.
(31) Klebe, G. Virtual ligand screening: strategies, perspectives and
limitations. Drug Discovery Today 2006, 11, 580–594.
(32) Mancera, R. L. Molecular modeling of hydration in drug design.
Curr. Opin. Drug Discovery Dev. 2007, 10, 275–280.
(33) Sousa, S. F.; Fernandes, P. A.; Ramos, M. J. Protein-ligand
docking: current status and future challenges. Proteins 2006, 65,
15–26.
(34) Babaoglu, K.; Shoichet, B. K. Deconstructing fragment-based
inhibitor discovery. Nat. Chem. Biol. 2006, 2, 720–723.
(35) Hajduk, P. J. Puzzling through fragment-based drug design. Nat.
Chem. Biol. 2006, 2, 658–659.
(36) Brenk, R.; Vetter, S. W.; Boyce, S. E.; Goodin, D. B.; Shoichet, B.
K. Probing molecular docking in a charged model binding site.
J. Mol. Biol. 2006, 357, 1449–1470.
(37) Gerber, P. R. Charge distribution from a simple molecular
orbital type calculation and nonbonding interaction terms in
the force field MAB. J. Comput.-Aided. Mol. Des. 1998, 12,
37–51.
(13) Hardy, L. W.; Matthews, W.; Nare, B.; Beverley, S. M.
Biochemical and Genetic Tests for Inhibitors of Leishmania Pter-
idine Pathways. Exp. Parasitol. 1997, 87, 158–170.
(38) Gerber, P. R.; Muller, K. MAB, a generally applicable molecular
force field for structure modelling in medicinal chemistry.
J. Comput.-Aided. Mol. Des. 1995, 9, 251–268.