Phytocompounds as potential inhibitors of p300-HIF1α interaction: A structure-based screening and molecular dynamics simulation analysis
Abstract
Hypoxia plays a key role in cancer progression, mainly by stabilizing and activating hypoxia-inducible
factor-1 (HIF-1) [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 [2,3]. Consequently, this study aimed to use drug designing 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. 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 molecular 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. 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.
DOI/handle
http://hdl.handle.net/10576/67189Collections
- Biomedical Research Center Research [832 items ]
- Laboratory Animal Research Center (Research) [136 items ]