Abstract

The treatment of ccRCC by targeting hypoxia-inducible factor HIF-2α is currently a direct and effective method. Studies have shown that HIF-2α and c-Myc cooperate to promote ccRCC tumor progression, and the overexpression of c-Myc is related to the progress and drug resistance of most human cancers. Although HIF-2α and c-Myc are important drug targets, their dual inhibitors are still lacking. We used virtual screening tools (mainly including molecular docking and MM-GBSA technology) to obtain some well-listed compounds that can potentially target HIF-2α and c-Myc and used molecular dynamics simulations to study their binding with these protein systems. Using a structure-based screening scheme, a batch of top-ranking compounds were selected, and their binding affinities were predicted of these compounds were performed. Representative compound C93106, C43257, and C41580 all showed good comprehensive binding score. Our results indicate that the target compounds can all form key interactions with the active site of the protein, and 30 ns molecular dynamic simulation of the complex system indicates a stable binding conformation. This research laid the foundation for the development of more effective and specific HIF-2α and c-Myc dual-target inhibitors.

摘要

靶向缺氧诱导因子HIF-2α治疗ccRCC是目前直接有效的方法。研究表明，HIF-2α和c-Myc协同促进ccRCC肿瘤进展，而c-Myc的过度表达与大多数人类癌症的进展和耐药性有关。虽然 HIF-2α 和 c-Myc 是重要的药物靶点，但它们的双重抑制剂仍然缺乏。我们使用虚拟筛选工具（主要包括分子对接和 MM-GBSA 技术）获得了一些可能靶向 HIF-2α 和 c-Myc 的化合物，并使用分子动力学模拟来研究它们与这些蛋白质系统的结合。使用基于结构的筛选方案，选择了一批排名靠前的化合物，并预测了它们与这些化合物的结合亲和力。代表化合物C93106、C43257和C41580均表现出良好的综合结合得分。我们的结果表明，目标化合物都可以与蛋白质的活性位点形成关键的相互作用，复杂系统的 30  ns分子动力学模拟表明具有稳定的结合构象。该研究为开发更有效和特异性的HIF-2α和c-Myc双靶点抑制剂奠定了基础。