Elucidating Hsp90α/β selectivity mechanisms via computer-aided drug design

作者：Shan Yang, Xinru Zhou, Xuanhe Xin, Yucheng Lu, Zhuo Zhang, Chao Ma, Mingming Zhao · 发表于：Molecular Simulation · 年份：2025 · DOI：10.1080/08927022.2025.2560950 · 被引用次数：1 · 研究领域：Heat shock proteins research、Protein Structure and Dynamics、Computational Drug Discovery Methods

Developing selective drugs is crucial for designing precise molecular inhibitors needed to treat diseases. However, the challenge of designing selective inhibitors for their targets, such as Hsp90α and Hsp90β, was exacerbated by the high similarity in sequence, domains and three-dimensional structure among protein subtypes. We elucidated the structural basis of isomeric selectivity between Hsp90α and Hsp90β using computational approaches. Despite the development of numerous Hsp90 inhibitor drugs, the high similarity between the two proteins meant that it was possible to inhibit Hsp90α/β, with the resultant adverse side effects. In order to investigate the selectivity of two isoforms, we selected the protein structures of Hsp90α (PDB ID: 7LSZ) and Hsp90β (PDB ID: 5UC4) and conducted a series of computational methods. It has been demonstrated that certain chemical modifications exhibit stable binding with critical amino acid sites, LEU107 (ΔΔG = 28.83 kcal/mol) and THR184 (ΔΔG = 43.96 kcal/mol) in Hsp90α, as well as LEU102 (ΔΔG = 31.09 kcal/mol) and GLY92 (ΔΔG = 46.35 kcal/mol) in Hsp90β. These interactions have been shown to significantly improve the targeting specificity between different Hsp90 proteins. In summary, these findings provided the foundation of the design of selective inhibitors for Hsp90α/β based on our investigation.