Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70

HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived HSP70 inhibitors potentially bind to the protein with a novel mechanism of action, the stabilization by desolvation of an intramolecular salt-bridge which induces a conformational change in the protein, leading to high affinity ligands. We also demonstrate that through the application of this mechanism, adenosine-derived HSP70 inhibitors can be optimized in a rational manner.

热休克蛋白70（HSP70）是一种分子伴侣，亦是热休克应答的核心组成部分。鉴于其在肿瘤学领域被认为具有重要研究价值，该蛋白已成为药物研发的热门靶点，但相关研究迄今尚未取得显著进展。本研究证实，腺苷衍生的热休克蛋白70抑制剂可通过全新作用机制与该蛋白结合：通过去溶剂化作用稳定分子内盐桥，进而诱导蛋白构象发生改变，最终生成高亲和力配体。本研究同时表明，依托该作用机制，可通过理性设计手段对腺苷衍生的热休克蛋白70抑制剂进行优化。