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

Bioorganic & Medicinal Chemistry
Farah El TurkHilal A Lashuel

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...Continue Reading

References

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Citations

Apr 23, 2013·Journal of Molecular Graphics & Modelling·Mahmoud A Al-Sha'erMutasem O Taha
Oct 8, 2013·PloS One·Ryan G ColemanBrian K Shoichet
Nov 24, 2011·Biochimica Et Biophysica Acta·Mayuko FukuokaKazuo Kuwata
Dec 1, 2015·Frontiers in Immunology·Tali LangJames Harris
Apr 18, 2015·Cytokine & Growth Factor Reviews·A N Gordon-WeeksR Muschel
May 10, 2016·Bioorganic & Medicinal Chemistry Letters·José A CisnerosWilliam L Jorgensen
Feb 21, 2014·Journal of Biomolecular Screening·Tsung-Lin Tsai, Thy-Hou Lin
May 31, 2018·Journal of Medicinal Chemistry·Vinay Trivedi-Parmar, William L Jorgensen

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