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Inflammation serves as a pivotal defense mechanism orchestrated by the innate immune system to safeguard cellular health against adversities. Nonetheless, dysregulated inflammatory responses can precipitate chronic inflammatory ailments, notably autoimmune disorders. Central to this process are various pathways, with studies highlighting the pivotal role of transcription factors within the nuclear factor-kappa B (NF-κB) signaling pathway in disease onset and progression. This study concentrates on the p50 homodimer protein, a key transcription factor pivotal for the expression of proinflammatory cytokine genes. To explore potential inhibitors of p50, we conducted in silico procedures to investigate fifty-eight unexplored compounds, derived from plants indigenous to the Philippines. Initial screenings for compound feasibility, through drug-likeness analyses, yielded positive outcomes for 34 compounds. Subsequent docking analyses revealed six compounds exhibiting binding energies (ranging from −3.7 to −4.2 kcal/mol) akin to or lower than the positive control, dexamethasone (−3.7 kcal/mol). These compounds include eudesm-11-en-4α-O-β-D-3-tigoyloxy-6-deoxy-glucopyranoside, wadeiol, grandiflorolide, eudesm-11-en-4α-O-β-D-3-senecioyloxy-6-deoxyglucopyranoside, α-pinene-7β-O-β-D-2- acetylglucopyranoside, and (2aβ,3α,5aβ,6β,7α,8aα)-6-[2-(3-furanyl)ethyl]-2a,3,4,5,5a,6,7,8,8a,8b- decahydro-2a,3-dihydroxy-6,7,8b-trimethyl-2H-naphtho[1-8-bc]furan-2-one. Interaction analyses revealed a common engagement of amino acid residues within the p50 DNA binding pocket, notably Arg57, Tyr60, Glu63, Lys244, Ala245, Pro246, Lys275, Arg308, Gln309, and Phe310, through hydrogen bonding, van der Waals forces, alkyl, and pi–alkyl interactions. Pharmacophore analysis underscored aromatic rings, hydroxyl, methyl, and methylene groups as pivotal for non-covalent interactions with p50. Additionally, root mean square fluctuation (RMSF) analysis demonstrated minimal residue fluctuations in p50 upon ligand binding compared to the ligand-free protein structure. In conclusion, the six shortlisted compounds exhibiting comparable binding affinities with dexamethasone hold promise as potential anti-inflammatory agents targeting the NF-κB p50 homodimer. [ABSTRACT FROM AUTHOR]