Document Type : Original Article
Authors
1
Department of Chemistry, Faculty of Science, Kosar University of Bojnord, P.O. Box: 9415615458, Bojnord, Iran
2
Research and Development Unit, Fakhar Industrial Group, Lotus Paint and Glaze Company, Rafsanjan, Iran
3
Department of Chemistry, University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran
4
Department of Chemistry, Faculty of Science, Hakim Sabzevari University, P. O. Box 9617976487, Sabzevar, Iran
10.22128/mch.2026.3317.1072
Abstract
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.
Keywords
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