Curcumin-based IKKβ inhibiting anticancer lead design using novel fragment-based group QSAR modelling

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.