Cheminformatics approaches to predict the bioactivity and to discover the pharmacophoric traits crucial to block NF-κB

• QSAR Analysis of structurally diverse molecules experimentally reported 503 compounds for IKKB inhibitory activity (IC 50 ) • Development of QSAR model using 503 compounds. • Use of Py-Descriptor. • Mechanistic interpretation. • Pharmacophore modeling and molecular docking study. • Comparison of QSAR results with pharmacophore modeling and molecular docking studies. • Stability studies by MD Simulation and MMGBSA analysis. Many human disorders include NF-kB signaling pathways, making IKK a therapeutic target in cancer treatment. Inflammatory illnesses and cancer are examples. COVID-19 is one of several triggers that stimulate NF-kB signaling. The activation of the NF-kB pathway is necessary for COVID-19 to cease its development. To learn more about the mechanism and structural features essential to IKK inhibition (IC 50 ), molecular modeling studies have been undertaken on experimentally reported 503. QSAR analysis explores certain reported and hidden structural features critical for IKKβ inhibition. The OECD guidelines guided the construction of the QSAR model, which achieved all the endorsed threshold values for all validation parameters (R 2 tr:0.81, R 2 LMO:0.80, and R 2 ext:0.78). The present QSAR study shows that IKK inhibitory activity is linked to the following structural features: lipophilic hydrogen atoms within 2 A units of the molecule's center of mass; ring nitrogen atoms within one bond of planar nitrogen atoms; ring carbon atoms exactly four bonds from the non-ring nitrogen atoms; planar nitrogen atoms exactly four bonds from sp2 hybridized carbon atoms; and so on. Pharmacophore modeling highlighted QSAR-identified structural characteristics. To investigate binding, we docked all 503 molecules. The observation indicates that the QSAR and molecular docking/pharmacophore modeling findings are in agreement. Following this, we conducted 200 ns of molecular dynamics simulation to validate the molecular docking protocol. MMGBSA analysis determined the binding energy of the dock complex. Thus, the current study found unique pharmacophoric properties that may assist in optimizing lead/hit compounds for anti-IKKβ activity.