64. Deng X, Gujjar R et al (2009) Structural plasticity of malaria dihydroorotate dehydrogenase
allows selective binding of diverse chemical scaffolds. J Biol Chem 284:26999–27009
65. Booker ML, Bastos CM et al (2010) Novel inhibitors of Plasmodium falciparum
dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. J Biol Chem
285:33054–33064
66. Coteron JM, Marco M et al (2011) Structure-guided lead optimization of triazolopyrimidinering substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase
inhibitors with clinical candidate potential. J Med Chem 54:5540–5561
67. Ross LS, Gamo FJ et al (2014) In vitro resistance selections for Plasmodium falciparum
dihydroorotate dehydrogenase inhibitors give mutants with multiple point mutations in the
drug-binding site and altered growth. J Biol Chem 289:17980–17995
68. Deng X, Kokkonda S et al (2014) Fluorine modulates species selectivity in the
triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors.
J Med Chem 57:5381–5394
69. Phillips MA, Lotharius J et al (2015) A long-duration dihydroorotate dehydrogenase inhibitor
(DSM265) for prevention and treatment of malaria. Sci Transl Med 7:296ra111
70. Deng X, Matthews D, Rathod PK, Phillips MA (2015) The X-ray structure of Plasmodium
falciparum dihydroorotate dehydrogenase bound to a potent and selective N-phenylbenzamide inhibitor reveals novel binding-site interactions. Acta Crystallogr Sec F 71:553–559
71. Kokkonda S, Deng X et al (2016) Tetrahydro-2-naphthyl and 2-indanyl triazolopyrimidines
targeting Plasmodium falciparum dihydroorotate dehydrogenase display potent and selective
antimalarial activity. J Med Chem 59:5416–5431
72. Phillips MA, White KL et al (2016) A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria.
ACS Infect Dis 2:945–957
73. Malmquist NA, Gujjar R, Rathod PK, Phillips MA (2008) Analysis of flavin oxidation and
electron-transfer inhibition in Plasmodium falciparum dihydroorotate dehydrogenase.
Biochemistry 47:2466–2475
74. [a] Norager S, Jensen KF, Björnberg O, Larsen S (2002) E. coli Dihydroorotate
dehydrogenase reveals structural and functional distinctions between different classes of
dihydroorotate dehydrogenases. structure 10:1211–1223; [b] Rowland P, Bjornberg O et al.
(1998) The crystal structure of Lactococcus lactis dihydroorotate dehydrogenase A
complexed with the enzyme reaction product throws light on its enzymatic function.
Protein Sci 7:1269–1279; [c] Rowland P, Nielsen FS, Jensen KF, Larsen S (1997) The crystal
structure of the flavin containing enzyme dihydroorotate dehydrogenase A from Lactococcus
lactis. Structure 5:239–252; [d] Sørensen PG, Dandanell G (2002) A new type of
dihydroorotate dehydrogenase, type 1S, from the thermoacidophilic archaeon Sulfolobus
solfataricus. Extremophiles 6:245–251
75. Bedingfield PT, Cowen D et al (2012) Factors influencing the specificity of inhibitor binding
to the human and malaria parasite dihydroorotate dehydrogenases. J Med Chem 55:5841–
5850
76. Copeland RA, Davis JP et al (1995) Recombinant human dihydroorotate dehydrogenase:
expression, purification, and characterization of a catalytically functional truncated enzyme.
Arch Biochem Biophys 323:79–86
77. [a] Löffler M, Knecht W et al. (2002) Drosophila melanogaster dihydroorotate dehydrogenase: the N-terminus is important for biological function in vivo but not for catalytic
properties in vitro. Insect Biochem Mol Biol 32:1159–1169; [b] Rawls J, Knecht W et al.
(2000) Requirements for the mitochondrial import and localization of dihydroorotate
dehydrogenase. Eur J Biochem 267:2079–2087
78. Phillips MA, Gujjar R et al (2008) Triazolopyrimidine-based dihydroorotate dehydrogenase
inhibitors with potent and selective activity against the malaria parasite Plasmodium
falciparum. J Med Chem 51:3649–3653
79. Heikkilä T, Ramsey C et al (2007) Design and synthesis of potent inhibitors of the malaria
parasite dihydroorotate dehydrogenase. J Med Chem 50:186–191
Structure-Based Design of PfDHODH Inhibitors …
219
allows selective binding of diverse chemical scaffolds. J Biol Chem 284:26999–27009
65. Booker ML, Bastos CM et al (2010) Novel inhibitors of Plasmodium falciparum
dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. J Biol Chem
285:33054–33064
66. Coteron JM, Marco M et al (2011) Structure-guided lead optimization of triazolopyrimidinering substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase
inhibitors with clinical candidate potential. J Med Chem 54:5540–5561
67. Ross LS, Gamo FJ et al (2014) In vitro resistance selections for Plasmodium falciparum
dihydroorotate dehydrogenase inhibitors give mutants with multiple point mutations in the
drug-binding site and altered growth. J Biol Chem 289:17980–17995
68. Deng X, Kokkonda S et al (2014) Fluorine modulates species selectivity in the
triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors.
J Med Chem 57:5381–5394
69. Phillips MA, Lotharius J et al (2015) A long-duration dihydroorotate dehydrogenase inhibitor
(DSM265) for prevention and treatment of malaria. Sci Transl Med 7:296ra111
70. Deng X, Matthews D, Rathod PK, Phillips MA (2015) The X-ray structure of Plasmodium
falciparum dihydroorotate dehydrogenase bound to a potent and selective N-phenylbenzamide inhibitor reveals novel binding-site interactions. Acta Crystallogr Sec F 71:553–559
71. Kokkonda S, Deng X et al (2016) Tetrahydro-2-naphthyl and 2-indanyl triazolopyrimidines
targeting Plasmodium falciparum dihydroorotate dehydrogenase display potent and selective
antimalarial activity. J Med Chem 59:5416–5431
72. Phillips MA, White KL et al (2016) A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria.
ACS Infect Dis 2:945–957
73. Malmquist NA, Gujjar R, Rathod PK, Phillips MA (2008) Analysis of flavin oxidation and
electron-transfer inhibition in Plasmodium falciparum dihydroorotate dehydrogenase.
Biochemistry 47:2466–2475
74. [a] Norager S, Jensen KF, Björnberg O, Larsen S (2002) E. coli Dihydroorotate
dehydrogenase reveals structural and functional distinctions between different classes of
dihydroorotate dehydrogenases. structure 10:1211–1223; [b] Rowland P, Bjornberg O et al.
(1998) The crystal structure of Lactococcus lactis dihydroorotate dehydrogenase A
complexed with the enzyme reaction product throws light on its enzymatic function.
Protein Sci 7:1269–1279; [c] Rowland P, Nielsen FS, Jensen KF, Larsen S (1997) The crystal
structure of the flavin containing enzyme dihydroorotate dehydrogenase A from Lactococcus
lactis. Structure 5:239–252; [d] Sørensen PG, Dandanell G (2002) A new type of
dihydroorotate dehydrogenase, type 1S, from the thermoacidophilic archaeon Sulfolobus
solfataricus. Extremophiles 6:245–251
75. Bedingfield PT, Cowen D et al (2012) Factors influencing the specificity of inhibitor binding
to the human and malaria parasite dihydroorotate dehydrogenases. J Med Chem 55:5841–
5850
76. Copeland RA, Davis JP et al (1995) Recombinant human dihydroorotate dehydrogenase:
expression, purification, and characterization of a catalytically functional truncated enzyme.
Arch Biochem Biophys 323:79–86
77. [a] Löffler M, Knecht W et al. (2002) Drosophila melanogaster dihydroorotate dehydrogenase: the N-terminus is important for biological function in vivo but not for catalytic
properties in vitro. Insect Biochem Mol Biol 32:1159–1169; [b] Rawls J, Knecht W et al.
(2000) Requirements for the mitochondrial import and localization of dihydroorotate
dehydrogenase. Eur J Biochem 267:2079–2087
78. Phillips MA, Gujjar R et al (2008) Triazolopyrimidine-based dihydroorotate dehydrogenase
inhibitors with potent and selective activity against the malaria parasite Plasmodium
falciparum. J Med Chem 51:3649–3653
79. Heikkilä T, Ramsey C et al (2007) Design and synthesis of potent inhibitors of the malaria
parasite dihydroorotate dehydrogenase. J Med Chem 50:186–191
Structure-Based Design of PfDHODH Inhibitors …
219