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PDBsum entry 6b2c
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Isomerase/isomerase inhibitor
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PDB id
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6b2c
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References listed in PDB file
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Key reference
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Title
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Adding a hydrogen bond may not help: naphthyridinone vs quinoline inhibitors of macrophage migration inhibitory factor.
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Authors
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T.K.Dawson,
P.Dziedzic,
M.J.Robertson,
J.A.Cisneros,
S.G.Krimmer,
A.S.Newton,
J.Tirado-Rives,
W.L.Jorgensen.
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Ref.
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ACS Med Chem Lett, 2017,
8,
1287-1291.
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PubMed id
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Abstract
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Coordination of the ammonium group of Lys32 in the active site of human
macrophage migration inhibitory factor (MIF) using a 1,7-naphthyridin-8-one
instead of a quinoline is investigated. Both gas- and aqueous-phase DFT
calculations for model systems indicate potential benefits for the added
hydrogen bond with the lactam carbonyl group, while FEP results are neutral.
Three crystal structures are reported for complexes of MIF
with3a,4a, and4b, which show that the desired hydrogen bond
is formed with O-N distances of 2.8-3.0 Å. Compound4bis the most potent
new MIF inhibitor withKiandKdvalues of 90
and 94 nM; it also has excellent aqueous solubility, 288 μg/mL. Consistent with
the FEP results, the naphthyridinones are found to have similar potency as
related quinolines in spite of the additional protein-ligand hydrogen bond.
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