利用分子动力学模拟研究拉索昔芬对 Y537S + F404V 双突变雌激素受体 Alpha 的疗效

IF 2.3 Q3 BIOCHEMICAL RESEARCH METHODS
Bioinformatics and Biology Insights Pub Date : 2024-10-08 eCollection Date: 2024-01-01 DOI:10.1177/11779322241288703
El Mehdi Bouricha, Mohammed Hakmi
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引用次数: 0

摘要

雌激素受体α(ERα)在乳腺癌(BC)进展过程中起着至关重要的作用,内分泌疗法是治疗ERα+BC的关键疗法。然而,ERα配体结合域(LBD)的体细胞突变往往会导致耐药性的产生。第三代选择性雌激素受体调节剂拉索昔芬(Lasofoxifene)已显示出对 Y537S 和 D538G 突变的耐药性。然而,在已存在 LBD 突变的患者中出现的新型 F404 突变引起了人们对其对拉索昔芬疗效影响的担忧。本研究调查了 Y537S 和 F404V 双突变对拉索昔芬药效的影响。通过分子动力学模拟和分子力学/泊松-玻尔兹曼表面积(MM-PBSA)自由能计算,我们发现双重突变降低了拉索昔芬的结合亲和力和结合自由能,破坏了关键的蛋白质-配体相互作用,并诱导配体结合袋发生显著的构象变化。这些变化很可能是由于 F404V 突变失去了 pi-pi 堆叠相互作用。这些发现表明,双重突变可能会降低拉索昔芬的药效。要证实这些结果并充分了解双重突变对拉索昔芬在ERα+转移性BC中疗效的影响,还需要进一步的实验验证。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Investigating Lasofoxifene Efficacy Against the Y537S + F404V Double-Mutant Estrogen Receptor Alpha Using Molecular Dynamics Simulations.

Estrogen receptor alpha (ERα) plays a critical role in breast cancer (BC) progression, with endocrine therapy being a key treatment for ERα + BC. However, resistance often arises due to somatic mutations in the ERα ligand-binding domain (LBD). Lasofoxifene, a third-generation selective estrogen receptor modulator, has shown promise against Y537S and D538G mutations. However, the emergence of a novel F404 mutation in patients with pre-existing LBD mutations raises concerns about its impact on lasofoxifene efficacy. This study investigates the impact of the dual Y537S and F404V mutations on lasofoxifene's efficacy. Using molecular dynamics simulations and molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) free energy calculations, we found that the dual mutation reduces lasofoxifene binding affinity and binding free energy, disrupts crucial protein-ligand interactions, and induces significant conformational changes in the ligand-binding pocket. These alterations are likely due to the loss of the pi-pi stacking interaction in the F404V mutation. These findings suggest a potential reduction in lasofoxifene efficacy due to the dual mutation. Further experimental validation is required to confirm these results and fully understand the impact of dual mutations on lasofoxifene's effectiveness in ERα + metastatic BC.

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来源期刊
Bioinformatics and Biology Insights
Bioinformatics and Biology Insights BIOCHEMICAL RESEARCH METHODS-
CiteScore
6.80
自引率
1.70%
发文量
36
审稿时长
8 weeks
期刊介绍: Bioinformatics and Biology Insights is an open access, peer-reviewed journal that considers articles on bioinformatics methods and their applications which must pertain to biological insights. All papers should be easily amenable to biologists and as such help bridge the gap between theories and applications.
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