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 speci...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2006, Vol.16 (1), p.88-92
Main Authors: Heikkilä, Timo, Thirumalairajan, Srinath, Davies, Matthew, Parsons, Mark R., McConkey, A. Glenn, Fishwick, Colin W.G., Johnson, A. Peter
Format: Article
Language:English
Subjects:
Animals
Antimalarials - chemical synthesis
Antimalarials - pharmacology
Biological and medical sciences
Catalysis
Chemistry, Pharmaceutical - methods
Computer Simulation
Crystallography, X-Ray
Drug Design
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Inhibitors
Inhibitory Concentration 50
Kinetics
Medical sciences
Medicinal chemistry
Miscellaneous
Models, Chemical
Models, Molecular
Molecular Conformation
Molecular modelling
Molecular recognition
Oxidoreductases Acting on CH-CH Group Donors - chemistry
Oxoreductases
Pharmacology. Drug treatments
Plasmodium falciparum - enzymology
Protein Conformation
Software
Substrate Specificity
Ubiquinone - chemistry
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Summary: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. 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.09.045