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Topological virtual screening: a way to find new compounds active in ulcerative colitis by inhibiting NF-κB

Molecular Diversity volume 15, pages 917–926 (2011)Cite this article

Abstract

Ulcerative colitis and Crohn’s disease are chronic, immune-mediated inflammatory diseases of the gastrointestinal tract. Nuclear Factor Kappa B (NF-κB) is a transcription factor that plays a key role in regulating expression of multiple inflammatory and immune genes. In this study, a Topological Virtual Screening study has been carried out to achieve a model capable of finding new compounds active in ulcerative colitis by inhibiting NF-κB. Different topological indices were used as structural descriptors, and their relation to biological activity was determined using linear discriminant analysis. A topological model consisting of two discriminant functions was built up. The first function focused in the discrimination between NF-κB active and inactive compounds, and the second one in distinguishing between compounds active and inactive on ulcerative colitis. The model was then applied sequentially to a large database of compounds with unknown activity. Twenty-eight of such compounds were predicted to be active and selected for in vitro and in vivo testing.

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Abbreviations

NF-κB:

Nuclear factor kappa B

IBD:

Inflammatory bowel disease

UC:

Ulcerative colitis

CD:

Crohn’s disease

TNF-α :

Tumor necrosis factor-α

IL:

Interleukin

LDA:

Linear discriminant analysis

HTS:

High throughput screening

QSAR:

Quantitative structure–activity relationship

DF:

Discriminant function

TI:

Topological indices

PDD:

Pharmacological distribution diagram

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Affiliations

  1. Molecular Connectivity and Drug Design Research Unit, Department of Physical Chemistry, Faculty of Pharmacy, University of Valencia, Avda. V.A. Estellés, s/n, 46100, Burjassot, Valencia, Spain

    María Gálvez-Llompart & Ramón García-Domenech

  2. Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Burjassot, Valencia, Spain

    María Gálvez-Llompart & María C. Recio

Authors
  1. María Gálvez-Llompart
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  2. María C. Recio
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  3. Ramón García-Domenech
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Correspondence to Ramón García-Domenech.

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Gálvez-Llompart, M., Recio, M.C. & García-Domenech, R. Topological virtual screening: a way to find new compounds active in ulcerative colitis by inhibiting NF-κB. Mol Divers 15, 917–926 (2011). https://doi.org/10.1007/s11030-011-9323-4

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  • DOI: https://doi.org/10.1007/s11030-011-9323-4

Keywords

  • NF-κB
  • Inflammatory bowel disease
  • Ulcerative colitis
  • Linear discriminant analysis
  • Molecular topology