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Discovery of novel potent nuclear factor kappa‐B inhibitors (IKK‐β) via extensive ligand‐based modeling and virtual screening
Author(s) -
AlSha'er Mahmoud A.,
Almazari Inas S.,
Taha Mutasem O.
Publication year - 2017
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/jmr.2604
Subject(s) - pharmacophore , loo , quantitative structure–activity relationship , iκb kinase , chemistry , virtual screening , kinase , kappa , stereochemistry , computational biology , transcription factor , biochemistry , mathematics , biology , geometry , gene
Inhibitor kappa‐B kinase‐beta (IKK‐β) controls the activation of nuclear transcription factor kappa‐B and has been linked to inflammation and cancer. Therefore, inhibitors of this kinase should have potent anti‐inflammatory and anticancer properties. Accordingly, we explored the pharmacophoric space of 218 IKK‐β inhibitors to identify high‐quality binding models. Subsequently, genetic algorithm‐based quantitative structure activity relationship (QSAR) analysis was employed to select the best possible combination of pharmacophoric models and physicochemical descriptors that explain bioactivity variation among training compounds. Three successful pharmacophores emerged in 2 optimal QSAR equations (r 1 2 175 = 0.733, r 1 2 LOO = 0.52, F1 = 65.62, r 1 2 PRESS against 43 test inhibitors = 0.63 and r 2 2 175 = 0.683, r 2 2 LOO = 0.52, F2 = 72.66, r 2 2 PRESS against 43 test inhibitors = 0.65). Two pharmacophores were merged in a single binding model. Receiver operating characteristic curve validation proved the excellent qualities of this model. The merged pharmacophore and the associated QSAR equations were applied to screen the National Cancer Institute list of compounds. Ten hits were found to exhibit potent anti‐IKK‐β bioactivity, out of which, one illustrates IC50 of 11.0nM.