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Optimization of Pyrazoles as Phenol Surrogates to Yield Potent Inhibitors of Macrophage Migration Inhibitory Factor.

Trivedi-Parmar V, Robertson MJ, Cisneros JA, Krimmer SG, Jorgensen WL
ChemMedChem 13 1092-1097 (2018)
Related entries: 6cbf, 6cbg, 6cbh

Cited: 6 times
EuropePMC logo PMID: 29575754

Abstract

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is implicated in the regulation of inflammation, cell proliferation, and neurological disorders. MIF is also an enzyme that functions as a keto-enol tautomerase. Most potent MIF tautomerase inhibitors incorporate a phenol, which hydrogen bonds to Asn97 in the active site. Starting from a 113-μm docking hit, we report results of structure-based and computer-aided design that have provided substituted pyrazoles as phenol alternatives with potencies of 60-70 nm. Crystal structures of complexes of MIF with the pyrazoles highlight the contributions of hydrogen bonding with Lys32 and Asn97, and aryl-aryl interactions with Tyr36, Tyr95, and Phe113 to the binding.

Reviews - 6cb5 mentioned but not cited (1)

  1. Ellagic Acid, Kaempferol, and Quercetin from Acacia nilotica: Promising Combined Drug With Multiple Mechanisms of Action. Al-Nour MY, Ibrahim MM, Elsaman T. Curr Pharmacol Rep 5 255-280 (2019)

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Articles citing this publication (4)

  1. Advances and Insights for Small Molecule Inhibition of Macrophage Migration Inhibitory Factor. Trivedi-Parmar V, Jorgensen WL. J Med Chem 61 8104-8119 (2018)
  2. Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti-Proliferative Activity in Lung Cancer Cells. Xiao Z, Song S, Chen D, van Merkerk R, van der Wouden PE, Cool RH, Quax WJ, Poelarends GJ, Melgert BN, Dekker FJ. Angew Chem Int Ed Engl 60 17514-17521 (2021)
  3. Absolute Free Energy of Binding Calculations for Macrophage Migration Inhibitory Factor in Complex with a Druglike Inhibitor. Qian Y, Cabeza de Vaca I, Vilseck JZ, Cole DJ, Tirado-Rives J, Jorgensen WL. J Phys Chem B 123 8675-8685 (2019)
  4. Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase Activity and Suppresses the Proliferation of Non-Small Cell Lung Cancer Cells. Xiao Z, Osipyan A, Song S, Chen D, Schut RA, van Merkerk R, van der Wouden PE, Cool RH, Quax WJ, Melgert BN, Poelarends GJ, Dekker FJ. J Med Chem 65 2059-2077 (2022)


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