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Title
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Virtual screening for inhibitors of the human TSLP:TSLPR interaction
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Author
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Abstract
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| The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) plays a pivotal role in the pathophysiology of various allergy disorders that are mediated by type 2 helper T cell (Th2) responses, such as asthma and atopic dermatitis. TSLP forms a ternary complex with the TSLP receptor (TSLPR) and the interleukin-7-receptor subunit alpha (IL-7Rα), thereby activating a signaling cascade that culminates in the release of pro-inflammatory mediators. In this study, we conducted an in silico characterization of the TSLP:TSLPR complex to investigate the drugability of this complex. Two commercially available fragment libraries were screened computationally for possible inhibitors and a selection of fragments was subsequently tested in vitro. The screening setup consisted of two orthogonal assays measuring TSLP binding to TSLPR: a BLI-based assay and a biochemical assay based on a TSLP:alkaline phosphatase fusion protein. Four fragments pertaining to diverse chemical classes were identified to reduce TSLP:TSLPR complex formation to less than 75% in millimolar concentrations. We have used unbiased molecular dynamics simulations to develop a Markov state model that characterized the binding pathway of the most interesting compound. This work provides a proof-of-principle for use of fragments in the inhibition of TSLP:TSLPR complexation. |
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Language
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English
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Source (journal)
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Scientific reports. - London, 2011, currens
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Publication
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London
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Nature Publishing Group
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2017
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ISSN
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2045-2322
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DOI
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10.1038/S41598-017-17620-7
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Volume/pages
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7
(2017)
, 9 p.
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Article Reference
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17211
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ISI
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000417463500010
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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Full text (open access)
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