کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10586190 | 981385 | 2010 | 16 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
An integrative in silico methodology for the identification of modulators of macrophage migration inhibitory factor (MIF) tautomerase activity
دانلود مقاله + سفارش ترجمه
دانلود مقاله ISI انگلیسی
رایگان برای ایرانیان
کلمات کلیدی
HTSSECF-scoreMolecular dynamics - دینامیک ملکولی یا پویایی مولکولیMIF - شهرMacrophage migration inhibitory factor - عامل مهارکننده مهاجرت ماکروفاژhigh-throughput screening - غربالگری بالاMALDI - مالدیwild-type - نوع وحشیLight scattering - پراکندگی نورSize exclusion chromatography - کروماتوگرافی اندازهای طردیmatrix-assisted laser desorption ionization - یونیزاسیون لیزر جذب ماتریس
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: An integrative in silico methodology for the identification of modulators of macrophage migration inhibitory factor (MIF) tautomerase activity An integrative in silico methodology for the identification of modulators of macrophage migration inhibitory factor (MIF) tautomerase activity](/preview/png/10586190.png)
چکیده انگلیسی
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 IC50 values lower than 10 μM (three hits with IC50 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, (IC50 = 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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 18, Issue 14, 15 July 2010, Pages 5425-5440
Journal: Bioorganic & Medicinal Chemistry - Volume 18, Issue 14, 15 July 2010, Pages 5425-5440
نویسندگان
Farah El Turk, Bruno Fauvet, Hajer Ouertatani-Sakouhi, Adrien Lugari, Stephane Betzi, Philippe Roche, Xavier Morelli, Hilal A. Lashuel,