Laboratory of Biological System Modeling, Centro de Desenvolvimento Tecnológico em Saúde (CDTS), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil.
Laboratório de Genômica Aplicada e Bioinovações, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil.
Int J Mol Sci. 2024 Aug 12;25(16):8782. doi: 10.3390/ijms25168782.
Drug repositioning is an important therapeutic strategy for treating breast cancer. Hsp90β chaperone is an attractive target for inhibiting cell progression. Its structure has a disordered and flexible linker region between the N-terminal and central domains. Geldanamycin was the first Hsp90β inhibitor to interact specifically at the N-terminal site. Owing to the toxicity of geldanamycin, we investigated the repositioning of ritonavir as an Hsp90β inhibitor, taking advantage of its proven efficacy against cancer. In this study, we used molecular modeling techniques to analyze the contribution of the Hsp90β linker region to the flexibility and interaction between the ligands geldanamycin, ritonavir, and Hsp90β. Our findings indicate that the linker region is responsible for the fluctuation and overall protein motion without disturbing the interaction between the inhibitors and the N-terminus. We also found that ritonavir established similar interactions with the substrate ATP triphosphate, filling the same pharmacophore zone.
药物重定位是治疗乳腺癌的一种重要治疗策略。Hsp90β伴侣蛋白是抑制细胞进展的一个有吸引力的靶点。其结构在 N 端和中央结构域之间具有无序和灵活的连接区。格尔德霉素是第一个特异性作用于 N 端位点的 Hsp90β 抑制剂。由于格尔德霉素的毒性，我们研究了利托那韦作为 Hsp90β 抑制剂的重定位，利用其对癌症的已证明疗效。在这项研究中，我们使用分子建模技术分析 Hsp90β 连接区对配体格尔德霉素、利托那韦和 Hsp90β 之间的灵活性和相互作用的贡献。我们的研究结果表明，连接区负责波动和整体蛋白质运动，而不干扰抑制剂与 N 端之间的相互作用。我们还发现利托那韦与底物三磷酸腺苷 (ATP) 建立了类似的相互作用，填补了相同的药效基团区域。
