title: Comparative protein modeling of 1-deoxy-D-xylulose-5-phosphate reductoisomerase enzyme from Plasmodium falciparum: a potential target for antimalarial drug discovery.
abstract: Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Pf-DXR) is a potential target for antimalarial chemotherapy. The three-dimensional model (3D) of this enzyme was determined by means of comparative modeling through multiple alignment followed by intensive optimization, minimization, and validation. The resulting model demonstrates a reasonable topology as gauged from the Ramachandran plot and acceptable three-dimensional structure compatibility as assessed by the Profiles-3D score. The modeled monomeric subunit consists of three domains: (1) N-terminal NADPH binding domain, (2) connective or linker domain (with most of the active site residues located in this domain), and (3) a C-terminal domain. This structure proved to be consistent with known DXR crystal structures from other species. The predicted active site compared favorably with those of the templates and appears to have an active site with a highly conserved architecture. Additionally, the model explains several site-directed mutagenesis data. Besides using several protein structure-checking programs to validate the model, a set of known inhibitors of DXR were also docked into the active site of the modeled Pf-DXR. The docked scores correlated reasonably well with experimental pIC50 values with a regression coefficient (R2) equal to 0.84. Results of the current study should prove useful in the early design and development of inhibitors by either de novo drug design or virtual screening of large small-molecule databases leading to development of new antimalarial agents.
authors.affiliation: Department of Medicinal Chemistry, Laboratory for Applied Drug Design and Synthesis, University of Mississippi, University, Mississippi 38677-1848, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Singh
authors.forename: Gwénaël
authors.initials: G
authors.lastname: Chevé
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011506:Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid
chemical_list: D000962:Antimalarials; D009097:Multienzyme Complexes; D011506:Proteins; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases