Medicinal Phytocompounds as Potential Inhibitors of p300-HIF1α Interaction: A Structure-Based Screening and Molecular Dynamics Simulation Study

<b>Background:</b> Hypoxia plays a key role in cancer progression, mainly by stabilizing and activating hypoxia-inducible factor-1 (HIF-1). For HIF-1 to function under low oxygen conditions, it must interact with the transcriptional coactivator p300, a critical step for promoting cancer cell survival and adaptation in hypoxic environments. <b>Methods:</b> Consequently, we used drug design and molecular simulation techniques to screen phytochemical databases, including traditional Chinese and African medicine sources, for compounds that could disrupt the p300/HIF-1 interaction. <b>Results:</b> In this study, we identified potential compounds with high docking scores such as EA-176920 (-8.719), EA-46881231 (-8.642), SA-31161 (-9.580), SA-5280863 (-8.179), NE-5280362 (-10.287), NE-72276 (-9.017), NA-11210533 (-10.366), NA-11336960 (-7.818), TCM-5281792 (-12.648), and TCM-6441280 (-9.470 kcal/mol) as lead compounds. Furthermore, the compound with the highest docking score from each database (EA-176920, SA-31161, NE-5280362, NA-11210533, and TCM-5281792) was subjected to further analysis. The stable binding affinity of these compounds with p300 was confirmed by Post-simulation binding free energy (-22.0020 kcal/mol, -25.4499 kcal/mol, -32.4530 kcal/mol, -33.9918 kcal/mol, and -57.7755 kcal/mol, respectively) and KD analysis. Moreover, the selected compounds followed the Lipinski rules with favorable ADMET properties like efficient intestinal absorption, high water solubility, and no toxicity. <b>Conclusions:</b> Our findings highlight the potential of natural compounds to target key protein-protein interactions in cancer and lay the groundwork for future in vitro and in vivo studies to explore their therapeutic potential. Specifically, disrupting the p300/HIF-1 interaction could interfere with hypoxia-driven pathways that promote tumor growth, angiogenesis, and metastasis, offering a promising strategy to suppress cancer progression at the molecular level.