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Virtual screening for inhibitors of the human TSLP:TSLPR interaction

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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-7Ra), 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-ofprinciple for use of fragments in the inhibition of TSLP: TSLPR complexation.
Keywords
THYMIC STROMAL LYMPHOPOIETIN, SCORING FUNCTION, FORCE-FIELD, HOT-SPOT, TSLP, DISCOVERY, COMPLEX, RESPONSES, RECEPTOR, ASTHMA

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Chicago
Van Rompaey, Dries, Kenneth Verstraete, Frank Peelman, Savvas Savvides, Koen Augustyns, Pieter Van Der Veken, and Hans De Winter. 2017. “Virtual Screening for Inhibitors of the Human TSLP:TSLPR Interaction.” Scientific Reports 7.
APA
Van Rompaey, D., Verstraete, K., Peelman, F., Savvides, S., Augustyns, K., Van Der Veken, P., & De Winter, H. (2017). Virtual screening for inhibitors of the human TSLP:TSLPR interaction. SCIENTIFIC REPORTS, 7.
Vancouver
1.
Van Rompaey D, Verstraete K, Peelman F, Savvides S, Augustyns K, Van Der Veken P, et al. Virtual screening for inhibitors of the human TSLP:TSLPR interaction. SCIENTIFIC REPORTS. 2017;7.
MLA
Van Rompaey, Dries, Kenneth Verstraete, Frank Peelman, et al. “Virtual Screening for Inhibitors of the Human TSLP:TSLPR Interaction.” SCIENTIFIC REPORTS 7 (2017): n. pag. Print.
@article{8542867,
  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-7Ra), 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-ofprinciple for use of fragments in the inhibition of TSLP: TSLPR complexation.},
  articleno    = {17211},
  author       = {Van Rompaey, Dries and Verstraete, Kenneth and Peelman, Frank and Savvides, Savvas and Augustyns, Koen and Van Der Veken, Pieter and De Winter, Hans},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  keyword      = {THYMIC STROMAL LYMPHOPOIETIN,SCORING FUNCTION,FORCE-FIELD,HOT-SPOT,TSLP,DISCOVERY,COMPLEX,RESPONSES,RECEPTOR,ASTHMA},
  language     = {eng},
  pages        = {9},
  title        = {Virtual screening for inhibitors of the human TSLP:TSLPR interaction},
  url          = {http://dx.doi.org/10.1038/s41598-017-17620-7},
  volume       = {7},
  year         = {2017},
}

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