title: The in silico screening and X-ray structure analysis of the inhibitor complex of Plasmodium falciparum orotidine 5'-monophosphate decarboxylase.
abstract: Orotidine 5'-monophosphate decarboxylase from Plasmodium falciparum (PfOMPDC) catalyses the final step in the de novo synthesis of uridine 5'-monophosphate (UMP) from orotidine 5'-monophosphate (OMP). A defective PfOMPDC enzyme is lethal to the parasite. Novel in silico screening methods were performed to select 14 inhibitors against PfOMPDC, with a high hit rate of 9%. X-ray structure analysis of PfOMPDC in complex with one of the inhibitors, 4-(2-hydroxy-4-methoxyphenyl)-4-oxobutanoic acid, was carried out to at 2.1 Å resolution. The crystal structure revealed that the inhibitor molecule occupied a part of the active site that overlaps with the phosphate-binding region in the OMP- or UMP-bound complexes. Space occupied by the pyrimidine and ribose rings of OMP or UMP was not occupied by this inhibitor. The carboxyl group of the inhibitor caused a dramatic movement of the L1 and L2 loops that play a role in the recognition of the substrate and product molecules. Combining part of the inhibitor molecule with moieties of the pyrimidine and ribose rings of OMP and UMP represents a suitable avenue for further development of anti-malarial drugs.
authors: Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yasuhide
authors: Y
authors: Takashima
authors: Eiichi
authors: E
authors: Mizohata
authors: Sudaratana R
authors: SR
authors: Krungkrai
authors: Yoshifumi
authors: Y
authors: Fukunishi
authors: Takayoshi
authors: T
authors: Kinoshita
authors: Tsuneaki
authors: T
authors: Sakata
authors: Hiroyoshi
authors: H
authors: Matsumura
authors: Jerapan
authors: J
authors: Krungkrai
authors: Toshihiro
authors: T
authors: Horii
authors: Tsuyoshi
authors: T
authors: Inoue
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D010654:Phenylbutyrates / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000201:enzymology*; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry; D013329:Structure-Activity Relationship; D014542:Uridine Monophosphate / Q000737:chemistry
chemical_list: C578186:4-(2-hydroxy-4-methoxyphenyl)-4-oxobutanoic acid; D000962:Antimalarials; D004791:Enzyme Inhibitors; D010654:Phenylbutyrates; D011743:Pyrimidines; D014542:Uridine Monophosphate; D009964:Orotidine-5'-Phosphate Decarboxylase; C030986:pyrimidine