The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase.
The de novo molecular design program SPROUT has been applied to the X-ray crystal structures of Plasmodium and human dihydroorotate dehydrogenase, respectively. The resulting design templates were used to prepare a series of molecules which, in keeping with predictions, showed useful levels of species-selective enzyme inhibition.
Heikkilä
Timo
T
School of Chemistry, University of Leeds, Leeds, England LS2 9JT, UK.
Thirumalairajan
Srinath
S
Davies
Matthew
M
Parsons
Mark R
MR
McConkey
A Glenn
AG
Fishwick
Colin W G
CW
Johnson
A Peter
AP
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000201:enzymology*; D011487:Protein Conformation; D012984:Software; D013379:Substrate Specificity; D014451:Ubiquinone / Q000737:chemistry
D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D014451:Ubiquinone; D044925:Oxidoreductases Acting on CH-CH Group Donors