Factors influencing the specificity of inhibitor binding to the human and malaria parasite dihydroorotate dehydrogenases
| Autor: | Paul Acklam, Deborah Cowen, Glenn A. McConkey, A. Peter Johnson, Paul T. P. Bedingfield, Colin W. G. Fishwick, Fraser Cunningham, Mark R. Parsons |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Oxidoreductases Acting on CH-CH Group Donors Protein Conformation Chemical structure Plasmodium falciparum Dihydroorotate Dehydrogenase Drug Evaluation Preclinical Ligands Substrate Specificity Small Molecule Libraries Inhibitory Concentration 50 Oxidoreductase Drug Discovery Humans Binding site Enzyme Inhibitors chemistry.chemical_classification biology biology.organism_classification Molecular biology Malaria Enzyme chemistry Biochemistry Docking (molecular) Pyrimidine metabolism Dihydroorotate dehydrogenase Mutagenesis Site-Directed Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 55(12) |
| ISSN: | 1520-4804 |
| Popis: | The de novo pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase is an emerging drug target for the treatment of malaria. In this context a key property of Plasmodium falciparum DHODH (PfDHODH) is that it can be selectively inhibited over its human homologue (HsDHODH). However, HsDHODH is also a validated drug target for autoimmune diseases such as arthritis. Here a series of novel inhibitors is described that includes compounds that switch specificity between the two enzymes as a result of small alterations in chemical structure. Structure–activity relationship (SAR), crystallography, docking, and mutagenesis studies are used to examine the binding modes of the compounds within the two enzymes and to reveal structural changes induced by inhibitor binding. Within this series, compounds with therapeutically relevant HsDHODH activity are described and their binding modes characterized using X-ray crystallography, which reveals a novel conformational shift within the inhibitor binding site. |
| Databáze: | OpenAIRE |
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