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Virtual screening and optimization yield low-nanomolar inhibitors of the tautomerase activity of Plasmodium falciparum macrophage migration inhibitory factor.

ABSTRACT: The Plasmodium falciparum orthologue of the human cytokine, macrophage migratory inhibitory factor (PfMIF), is produced by the parasite during malaria infection and modulates the host's immune response. As for other MIF orthologues, PfMIF has tautomerase activity, whose inhibition may influence the cytokine activity. To identify small-molecule inhibitors of the tautomerase activity of PfMIF, virtual screening has been performed by docking 2.1 million compounds into the enzymatic site. Assaying of 17 compounds identified four as active. Substructure search for the most potent of these compounds, a 4-phenoxypyridine analogue, identified four additional compounds that were purchased and also shown to be active. Thirty-one additional analogues were then designed, synthesized, and assayed. Three were found to be potent PfMIF tautomerase inhibitors with K(i) of ?40 nM; they are also highly selective with K(i) > 100 ?M for human MIF.

SUBMITTER: Dahlgren MK

PROVIDER: S-EPMC3509768 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Virtual screening and optimization yield low-nanomolar inhibitors of the tautomerase activity of Plasmodium falciparum macrophage migration inhibitory factor.

Dahlgren Markus K MK Baeza Garcia Alvaro A Hare Alissa A AA Tirado-Rives Julian J Leng Lin L Bucala Richard R Jorgensen William L WL

Journal of medicinal chemistry 20121026 22

The Plasmodium falciparum orthologue of the human cytokine, macrophage migratory inhibitory factor (PfMIF), is produced by the parasite during malaria infection and modulates the host's immune response. As for other MIF orthologues, PfMIF has tautomerase activity, whose inhibition may influence the cytokine activity. To identify small-molecule inhibitors of the tautomerase activity of PfMIF, virtual screening has been performed by docking 2.1 million compounds into the enzymatic site. Assaying o ...[more]

PMID: 23067344

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Project description:BackgroundThe human (Homo sapiens) chemokine-like protein macrophage migration inhibitory factor (HsMIF) is a pivotal mediator of inflammatory, infectious and immune diseases including septic shock, colitis, malaria, rheumatoid arthritis, and atherosclerosis, as well as tumorigenesis. HsMIF has been found to exhibit several sequential and three-dimensional sequence motifs that in addition to its receptor binding sites include catalytic sites for oxidoreductase and tautomerase activity, which provide this 12.5 kDa protein with a remarkable functional complexity. A human MIF paralog, D-dopachrome tautomerase (HsDDT), has been identified, but its physiological relevance is incompletely understood. MIF/DDT-like proteins have been described in animals, protists and bacteria. Although based on sequence data banks the presence of MIF/DDT-like proteins has also been recognized in the model plant species Arabidopsis thaliana, details on these plant proteins have not been reported.ResultsTo broaden the understanding of the biological role of these proteins across kingdoms we performed a comprehensive in silico analysis of plant MIF/DDT-like (MDL) genes/proteins. We found that the A. thaliana genome harbors three MDL genes, of which two are chiefly constitutively expressed in aerial plant organs, while the third gene shows stress-inducible transcript accumulation. The product of the latter gene likely localizes to peroxisomes. Structure prediction suggests that all three Arabidopsis proteins resemble the secondary and tertiary structure of human MIF. MIF-like proteins are found in all species across the plant kingdom, with an increasing family complexity towards evolutionarily advanced plant taxa. Plant MDL proteins are predicted to lack oxidoreductase activity, but possibly share tautomerase activity with human MIF/DDT.ConclusionsPeroxisome localization seems to be a specific feature of a subset of MIF/DDT orthologs found in dicotyledonous plant species, which together with its stress-inducible gene expression might point to convergent evolution in higher plants and vertebrates towards neofunctionalization of MIF/MDL proteins in stress response pathways including innate immunity.

Dataset Information

Virtual screening and optimization yield low-nanomolar inhibitors of the tautomerase activity of Plasmodium falciparum macrophage migration inhibitory factor.

Publications

Virtual screening and optimization yield low-nanomolar inhibitors of the tautomerase activity of Plasmodium falciparum macrophage migration inhibitory factor.

Similar Datasets

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