An integrative in silico methodology for the identification of modulators of macrophage migration inhibitory factor (MIF) tautomerase activity

Farah El Turk, Bruno Fauvet, Hajer Ouertatani-Sakouhi, Adrien Lugari, Stephane Betzi, Philippe Roche, Xavier Morelli, Hilal A. Lashuel

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Macrophage migration inhibitory factor (MIF) is a major proinflammatory cytokine that has been increasingly implicated in the pathogenesis of several inflammatory, autoimmune, infectious and oncogenic diseases. Accumulating evidence suggests that the tautomerase activity of MIF plays a role in modulating some of its intra- and extra-cellular activities. Therefore, the identification and development of small-molecule inhibitors targeting the catalytic activity of MIF has emerged as an attractive and viable therapeutic strategy to attenuate its function in health and disease. Herein we report a novel virtual screening protocol for the discovery of new inhibitors of MIF's tautomerase activity. Our protocol takes into account the flexibility and dynamics of the catalytic site by coupling molecular dynamics (MD) simulations aimed at modeling the protein's flexibility in solution to (i) docking with FlexX, or (ii) docking with FlexX and pharmacophoric filtering with Unity. In addition, we applied in parallel a standalone docking using the new version of Surflex software. The three approaches were used to screen the ChemBridge chemical library and the inhibitory activity of the top-ranked 333 compound obtained from each approach (1000 compound in total) was assessed in vitro using the tautomerase assay. This biochemical validation process resulted in the identification of 12 novel MIF inhibitors corresponding to a 1.2% hit rate. Six of these hits came from Surflex docking; two from FlexX docking with MD simulations and four hits were identified with MDS and pharmacophore filtering with minimal overlap between the hits from each approach. Six hits were identified with IC 50 values lower than 10 μM (three hits with IC 50 lower than 1 μM); four were shown to be suicide inhibitors and act via covalent modification of the N-terminal catalytic residues Pro1. One additional inhibitor, N-phenyl-N-1,3,4-thiadiazol-2-yl-thiourea, (IC 50 = 300 nM) was obtained from FlexX docking combined to pharmacophoric filtering on one of the eight MD structures. These results demonstrate the power of integrative in silico approaches in the discovery of new modulator of MIF's tautomerase activity. The chemical diversity and mode of action of these compounds suggest that they could be used as molecular probes to elucidate the functions and biology of MIF and as lead candidates in drug developments of anti-MIF drugs.

Original languageEnglish
Pages (from-to)5425-5440
Number of pages16
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number14
DOIs
Publication statusPublished - 15 Jul 2010
Externally publishedYes

Fingerprint

Macrophage Migration-Inhibitory Factors
Molecular Dynamics Simulation
Computer Simulation
Modulators
Biochemical Phenomena
Small Molecule Libraries
Molecular dynamics
Molecular Probes
Thiourea
Molecular Structure
Pharmaceutical Preparations
Suicide
Communicable Diseases
Catalytic Domain
Software
Cytokines
Health
Computer simulation
Assays
Catalyst activity

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

An integrative in silico methodology for the identification of modulators of macrophage migration inhibitory factor (MIF) tautomerase activity. / Turk, Farah El; Fauvet, Bruno; Ouertatani-Sakouhi, Hajer; Lugari, Adrien; Betzi, Stephane; Roche, Philippe; Morelli, Xavier; Lashuel, Hilal A.

In: Bioorganic and Medicinal Chemistry, Vol. 18, No. 14, 15.07.2010, p. 5425-5440.

Research output: Contribution to journalArticle

Turk, Farah El ; Fauvet, Bruno ; Ouertatani-Sakouhi, Hajer ; Lugari, Adrien ; Betzi, Stephane ; Roche, Philippe ; Morelli, Xavier ; Lashuel, Hilal A. / An integrative in silico methodology for the identification of modulators of macrophage migration inhibitory factor (MIF) tautomerase activity. In: Bioorganic and Medicinal Chemistry. 2010 ; Vol. 18, No. 14. pp. 5425-5440.
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