Shi Danfeng, Bai Qifeng, Zhou Shuangyan, Liu Xuewei, Liu Huanxiang, Yao Xiaojun
Department of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China.
Proteins. 2018 Jan;86(1):43-56. doi: 10.1002/prot.25401. Epub 2017 Oct 26.
As co-chaperones of the 90-kDa heat shock protein(HSP90), FK506 binding protein 51 (FKBP51) and FK506 binding protein 52 (FKBP52) modulate the maturation of steroid hormone receptor through their specific FK1 domains (FKBP12-like domain 1). The inhibitors targeting FK1 domains are potential therapies for endocrine-related physiological disorders. However, the structural conservation of the FK1 domains between FKBP51 and FKBP52 make it difficult to obtain satisfactory selectivity in FK506-based drug design. Fortunately, a series of iFit ligands synthesized by Hausch et al exhibited excellent selectivity for FKBP51, providing new opportunity for design selective inhibitors. We performed molecular dynamics simulation, binding free energy calculation and unbinding pathway analysis to reveal selective mechanism for the inhibitor iFit4 binding with FKBP51 and FKBP52. The conformational stability evaluation of the "Phe67-in" and "Phe67-out" states implies that FKBP51 and FKBP52 have different preferences for "Phe67-in" and "Phe67-out" states, which we suggest as the determinant factor for the selectivity for FKBP51. The binding free energy calculations demonstrate that nonpolar interaction is favorable for the inhibitors binding, while the polar interaction and entropy contribution are adverse for the inhibitors binding. According to the results from binding free energy decomposition, the electrostatic difference of residue 85 causes the most significant thermodynamics effects on the binding of iFit4 to FKBP51 and FKBP52. Furthermore, the importance of substructure units on iFit4 were further evaluated by unbinding pathway analysis and residue-residue contact analysis between iFit4 and the proteins. The results will provide new clues for the design of selective inhibitors for FKBP51.
作为90 kDa热休克蛋白（HSP90）的共伴侣蛋白，FK506结合蛋白51（FKBP51）和FK506结合蛋白52（FKBP52）通过其特定的FK1结构域（类FKBP12结构域1）调节类固醇激素受体的成熟。靶向FK1结构域的抑制剂是治疗内分泌相关生理紊乱的潜在疗法。然而，FKBP51和FKBP52之间FK1结构域的结构保守性使得在基于FK506的药物设计中难以获得令人满意的选择性。幸运的是，Hausch等人合成的一系列iFit配体对FKBP51表现出优异的选择性，为设计选择性抑制剂提供了新机会。我们进行了分子动力学模拟、结合自由能计算和解离途径分析，以揭示抑制剂iFit4与FKBP51和FKBP52结合的选择性机制。“Phe67-内”和“Phe67-外”状态的构象稳定性评估表明，FKBP51和FKBP52对“Phe67-内”和“Phe67-外”状态有不同的偏好，我们认为这是对FKBP51选择性的决定因素。结合自由能计算表明，非极性相互作用有利于抑制剂结合，而极性相互作用和熵贡献不利于抑制剂结合。根据结合自由能分解结果，残基85的静电差异对iFit4与FKBP51和FKBP52结合产生最显著的热力学效应。此外，通过iFit4与蛋白质之间的解离途径分析和残基-残基接触分析，进一步评估了iFit4上亚结构单元的重要性。这些结果将为设计FKBP51选择性抑制剂提供新线索。
