Virtual screening for inhibitors of the human TSLP:TSLPR interaction. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Van Rompaey, Dries; Verstraete, Kenneth; Peelman, Frank; Savvides, Savvas; Augustyns, Koen; Van Der Veken, Pieter; De Winter, Hans
• Is Part Of: Scientific reports. Volume 7:Issue 1(2017)
• Page Start: 1
• Page End: 9
• Publication Date: 2017-12
• Subjects: Natural history -- Research -- Periodicals; Biology -- Research -- Periodicals; Physical sciences -- Research -- Periodicals; Earth sciences -- Research -- Periodicals; Environmental sciences -- Research -- Periodicals; 502.85
• DOI: 10.1038/s41598-017-17620-7
• Languages: English
• ISSNs: 2045-2322

Abstract

Abstract 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 anin 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 testedin 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.