Virtual screening and optimization yield low-nanomolar inhibitors of the tautomerase activity of Plasmodium falciparum macrophage migration inhibitory factor.
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) &gt; 100 μM for human MIF.
Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, USA.
Markus K
MK
Dahlgren
Alvaro
A
Baeza Garcia
Alissa A
AA
Hare
Julian
J
Tirado-Rives
Lin
L
Leng
Richard
R
Bucala
William L
WL
Jorgensen
D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D006860:Hydrogen Bonding; D007535:Isomerases / Q000037:antagonists & inhibitors*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors*; D008288:Malaria / Q000188:drug therapy* / Q000378:metabolism / Q000469:parasitology; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D008263:Macrophage Migration-Inhibitory Factors; D015800:Protozoan Proteins; D054852:Small Molecule Libraries; C519265:macrophage-migration inhibitory factor, Plasmodium falciparum; D007535:Isomerases