Adding a Hydrogen Bond May Not Help: Naphthyridinone vs Quinoline Inhibitors of Macrophage Migration Inhibitory Factor.
Publication Type:Journal Article
Source:ACS Med Chem Lett, Volume 8, Issue 12, p.1287-1291 (2017)
<p>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,, and, which show that the desired hydrogen bond is formed with O-N distances of 2.8-3.0 Å. Compoundis the most potent new MIF inhibitor withandvalues 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.</p>