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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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