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

Abstract

NF-κB 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-κB is strictly controlled by IκB kinase, and therefore IκB kinase inhibition forms the basis for anticancer drug research. We present here a novel fragment-based QSAR model using 4-arylidene curcumin analogues having IκB kinase inhibitory properties. The insights into the contribution of each chemical fragment of the analogues in IκB 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 IκB 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 IκB 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.