Journal
MEDICINAL CHEMISTRY RESEARCH
Volume 24, Issue 5, Pages 2022-2032Publisher
SPRINGER BIRKHAUSER
DOI: 10.1007/s00044-014-1274-8
Keywords
Transcription factor; NF-kappa B; I kappa B kinase; Anticancer; Curcumin; QSAR; Simulations
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NF-kappa B transcription factor plays a vital role in the protection of transformed cells from apoptosis, thus resulting in the onset/progression of cancer. Activation of NF-kappa B is strictly controlled by I kappa B kinase, and therefore I kappa B kinase inhibition forms the basis for anticancer drug research. We present here a novel fragment-based QSAR model using 4-arylidene curcumin analogues having I kappa B kinase inhibitory properties. The insights into the contribution of each chemical fragment of the analogues in I kappa B kinase inhibitory activity were used to generate a combinatorial library containing 167,828 molecules and their inhibitory activities were predicted by the reported G-QSAR model. We report top two scoring compounds BEP and BHP possessing high docking scores of -9.21 and -8.98 kcal/mol, respectively. Molecular dynamics simulations studies showed that the trajectories of the I kappa B kinase complexed with BEP and BHP were stable over a considerably long time period (16 ns). The two compounds reported here showed high binding affinity and stability with I kappa B kinase and thus can be taken forward as promising anticancer leads. The G-QSAR model reported here will pave way for the development of novel leads by high-throughput activity prediction of similar compounds.
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