The malarial drug target Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR): development of a 3-D model for identification of novel, structural and functional features and for inhibitor screening

Jessica L Goble; Matthew R Adendorff; Tjaart A P de Beer; Linda L Stephens; Gregory L Blatch

doi:10.2174/092986610789909548

The malarial drug target Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR): development of a 3-D model for identification of novel, structural and functional features and for inhibitor screening

Protein Pept Lett. 2010 Jan;17(1):109-20. doi: 10.2174/092986610789909548.

Authors

Jessica L Goble¹, Matthew R Adendorff, Tjaart A P de Beer, Linda L Stephens, Gregory L Blatch

Affiliation

¹ Biomedical Biotechnology Research Unit, Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, Grahamstown 6140, South Africa.

PMID: 20214634
DOI: 10.2174/092986610789909548

Abstract

A three-dimensional model of the malarial drug target protein PfDXR was generated, and validated using structure-checking programs and protein docking studies. Structural and functional features unique to PfDXR were identified using the model and comparative sequence analyses with apicomplexan and non-apicomplexan DXR proteins. Furthermore, we have used the model to develop an efficient approach to screen for potential tool compounds for use in the rational design of novel DXR inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aldose-Ketose Isomerases / antagonists & inhibitors
Aldose-Ketose Isomerases / chemistry*
Aldose-Ketose Isomerases / genetics
Aldose-Ketose Isomerases / metabolism
Amino Acid Sequence
Antimalarials / chemistry
Antimalarials / pharmacology
Catalytic Domain
Drug Delivery Systems / methods*
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Fosfomycin / analogs & derivatives
Fosfomycin / chemistry
Fosfomycin / pharmacology
Inhibitory Concentration 50
Models, Molecular
Molecular Sequence Data
Multienzyme Complexes / antagonists & inhibitors
Multienzyme Complexes / chemistry*
Multienzyme Complexes / genetics
Multienzyme Complexes / metabolism
Oxidoreductases / antagonists & inhibitors
Oxidoreductases / chemistry*
Oxidoreductases / genetics
Oxidoreductases / metabolism
Plasmodium falciparum / enzymology*
Protein Binding
Reproducibility of Results
Sequence Alignment
Structure-Activity Relationship

Substances

Antimalarials
Enzyme Inhibitors
Multienzyme Complexes
Fosfomycin
fosmidomycin
Oxidoreductases
1-deoxy-D-xylulose 5-phosphate reductoisomerase
Aldose-Ketose Isomerases