inhibiting nf-κb activation and reversing multidrug resistance via directly targeting the dna-binding loop of p50 by small molecules

Uncontrolled nuclear factor-κb (nf-κb) pathway activation is directly involved in cancer development, inflammation, and multidrug resistance, yet potent direct inhibitors remain limited. herein, we employed a fragment-based design strategy to develop structurally optimized chromone analogs by combining fragments derived from natural nf-κb inhibitors. unlike previous studies that mainly focused on indirect inhibition pathways, our strategy specifically targeted the dna-binding loop of the p50 subunit, a region essential for transcriptional regulation. optimized geometries (b3lyp/6-31+g(d)) and fragment-based ligand variants were manually constructed, followed by automated docking into nf-κb p50 using autodock 4.2. binding energies calculated for residues 356–368 identified several promising candidates. docking studies demonstrated that some designed molecules exhibited stronger binding affinity (up to −11.13 kcal.mol⁻¹, ki = 6.9 nm) than known reference inhibitors. importantly, these compounds selectively inhibited nf-κb while sparing pi3k activity, thereby minimizing potential off-target effects. furthermore, the fragment-based designed compounds showed favorable interactions with p-glycoprotein, suggesting their potential to reverse multidrug resistance. these findings introduce a rationally designed family of small molecules with dual potential for direct nf-κb inhibition and modulation of multidrug resistance.