Quantitative structure-activity relationship and molecular docking studies on human proteasome inhibitors for anticancer activity targeting NF-κB signaling pathway

The abnormal ubiquitin-proteasome is found as an important target in various human diseases, especially in cancer, and recently it has received prevalent attention as a challenging therapeutic target. The current work is designed to derive a predictive two-dimensional quantitative structure-activity relationship model for anticancer human proteasome target of NF-κB signaling pathway. The established 2 D-QSAR is dependent on multiple linear regression approach and validated through leave-One-Out and external test set prediction method. The robust QSAR model showed the r² of 0.83 and q² of 0.80 and pred_r² of 0.77. Three chemical properties, electronegativity count, average potential, and T_2_N_6 were identified as significant descriptors to predict the anticancer activities of the proteasome antagonists. Besides, the predicted top hit compounds were considered to check out the compliance with Rule of five and pharmacokinetic parameters for oral bioavailability in the human body. The molecular docking was accomplished to unravel the molecular mode of action of best-predicted compounds which was compatible with the standard drug. Following this approach, lastly two compounds NP and AP were recognized as the best candidates since these top compounds follow all the standard limit point of entire filters and indicated effective and decent docking score. The outcomes of the study sturdily suggested that the developed model and top hit compound’s binding conformation are rational in the exploration of unknown antagonist’s anticancer activity. The research would be of great support and is supposed to be of immense significance in the development and designing of drug-like candidates in preliminary drug discovery. Communicated by Ramaswamy H. Sarma