Suleman Muhammad, Sayaf Abrar Mohammad, Aftab Sohail, Alissa Mohammed, Alghamdi Abdullah, Alghamdi Suad A, Alshehri Mohammed A, Yeoh Kar Kheng, Crovella Sergio, Shaito Abdullah A
Laboratory of Animal Research Center (LARC), Qatar University, Doha P.O. Box 2713, Qatar.
Center for Biotechnology and Microbiology, University of Swat, Swat 19200, Pakistan.
Pharmaceuticals (Basel). 2025 Apr 21;18(4):602. doi: 10.3390/ph18040602.
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. 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. 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. 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.
缺氧在癌症进展中起着关键作用，主要是通过稳定和激活缺氧诱导因子-1（HIF-1）来实现。为了使HIF-1在低氧条件下起作用，它必须与转录共激活因子p300相互作用，这是促进癌细胞在缺氧环境中存活和适应的关键步骤。因此，我们使用药物设计和分子模拟技术，在包括传统中药和非洲药物来源的植物化学数据库中筛选能够破坏p300/HIF-1相互作用的化合物。在本研究中，我们鉴定出具有高对接分数的潜在化合物，如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-1133,6960（-7.818）、TCM-5281792（-12.648）和TCM-6441280（-9.470千卡/摩尔）作为先导化合物。此外，对每个数据库中对接分数最高的化合物（EA-176920、SA-31161、NE-5280362、NA-11210533和TCM-5281792）进行了进一步分析。通过模拟后结合自由能（分别为-22.0020千卡/摩尔、-25.4499千卡/摩尔、-32.4530千卡/摩尔、-33.9918千卡/摩尔和-57.7755千卡/摩尔）和KD分析，证实了这些化合物与p300具有稳定的结合亲和力。此外，所选化合物符合Lipinski规则，具有良好的ADMET性质，如高效的肠道吸收、高水溶性和无毒性。我们的研究结果突出了天然化合物靶向癌症中关键蛋白质-蛋白质相互作用的潜力，并为未来探索其治疗潜力的体外和体内研究奠定了基础。具体而言，破坏p300/HIF-1相互作用可能会干扰促进肿瘤生长、血管生成和转移的缺氧驱动途径，为在分子水平上抑制癌症进展提供了一种有前景的策略。
