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The in silico screening and X-ray structure analysis of the inhibitor complex of Plasmodium falciparum orotidine 5'-monophosphate decarboxylase.
J Biochem. 2012 Aug; 152(2):133-8.JB

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.

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Authors+Show Affiliations

Takashima Y
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Mizohata E
No affiliation info available
Krungkrai SR
No affiliation info available
Fukunishi Y
No affiliation info available
Kinoshita T
No affiliation info available
Sakata T
No affiliation info available
Matsumura H
No affiliation info available
Krungkrai J
No affiliation info available
Horii T
No affiliation info available
Inoue T
No affiliation info available

MeSH

AntimalarialsBinding SitesCatalytic DomainComputer SimulationCrystallography, X-RayDrug Evaluation, PreclinicalEnzyme InhibitorsModels, MolecularOrotidine-5'-Phosphate DecarboxylasePhenylbutyratesPlasmodium falciparumProtein ConformationPyrimidinesStructure-Activity RelationshipUridine Monophosphate

Pub Type(s)

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

Language

eng

PubMed ID

22740703

Citation

Takashima, Yasuhide, et al. "The in Silico Screening and X-ray Structure Analysis of the Inhibitor Complex of Plasmodium Falciparum Orotidine 5'-monophosphate Decarboxylase." Journal of Biochemistry, vol. 152, no. 2, 2012, pp. 133-8.
Takashima Y, Mizohata E, Krungkrai SR, et al. The in silico screening and X-ray structure analysis of the inhibitor complex of Plasmodium falciparum orotidine 5'-monophosphate decarboxylase. J Biochem. 2012;152(2):133-8.
Takashima, Y., Mizohata, E., Krungkrai, S. R., Fukunishi, Y., Kinoshita, T., Sakata, T., Matsumura, H., Krungkrai, J., Horii, T., & Inoue, T. (2012). The in silico screening and X-ray structure analysis of the inhibitor complex of Plasmodium falciparum orotidine 5'-monophosphate decarboxylase. Journal of Biochemistry, 152(2), 133-8.
Takashima Y, et al. The in Silico Screening and X-ray Structure Analysis of the Inhibitor Complex of Plasmodium Falciparum Orotidine 5'-monophosphate Decarboxylase. J Biochem. 2012;152(2):133-8. PubMed PMID: 22740703.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The in silico screening and X-ray structure analysis of the inhibitor complex of Plasmodium falciparum orotidine 5'-monophosphate decarboxylase. AU - Takashima,Yasuhide, AU - Mizohata,Eiichi, AU - Krungkrai,Sudaratana R, AU - Fukunishi,Yoshifumi, AU - Kinoshita,Takayoshi, AU - Sakata,Tsuneaki, AU - Matsumura,Hiroyoshi, AU - Krungkrai,Jerapan, AU - Horii,Toshihiro, AU - Inoue,Tsuyoshi, Y1 - 2012/06/26/ PY - 2012/6/29/entrez PY - 2012/6/29/pubmed PY - 2013/2/13/medline SP - 133 EP - 8 JF - Journal of biochemistry JO - J Biochem VL - 152 IS - 2 N2 - 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. SN - 1756-2651 UR - https://www.unboundmedicine.com/medline/citation/22740703/The_in_silico_screening_and_X_ray_structure_analysis_of_the_inhibitor_complex_of_Plasmodium_falciparum_orotidine_5'_monophosphate_decarboxylase_ L2 - https://academic.oup.com/jb/article-lookup/doi/10.1093/jb/mvs070 DB - PRIME DP - Unbound Medicine ER -