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Adding a Hydrogen Bond May Not Help: Naphthyridinone vs Quinoline Inhibitors of Macrophage Migration Inhibitory Factor

Journal Article · · ACS Medicinal Chemistry Letters
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  1. Yale Univ., New Haven, CT (United States)
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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 with 3a, 4a, and 4b, which show that the desired hydrogen bond is formed with O–N distances of 2.8–3.0 Å. Compound 4b is the most potent new MIF inhibitor with Ki and Kd values 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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (US). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); National Science Foundation (NSF); USDOE
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1430309
Journal Information:
ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 12 Vol. 8; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Figures / Tables (8)

Figure 1(p. 2)figure Figure 1
Figure 2(p. 2)figure Figure 2
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Figure 4(p. 2)figure Figure 4
Scheme 1(p. 2)figure Scheme 1
Figure 5(p. 3)figure Figure 5
Table 1(p. 3)table Table 1
Figure 6(p. 4)figure Figure 6

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Carbonyls
Inhibitors
MIF inhibitors
Molecules
Noncovalent interactions
Peptides and proteins
lysine coordination
protein crystallography