【佳学基因靶向药物基因检测】通过分子动力学模拟深入了解 pralsetinib 对非看门人 RET 激酶 G810C 突变的耐药性

深圳品牌检测基因费用香港

可知检测结果分析中的基因解码方法发现《J Mol Model》在 2022 Dec 28;29(1):24.发表了一篇题目为《》肿瘤靶向药物治疗基因检测临床研究文章。该研究由Shu Cao, Changbin Tan, Anhua Fei, Gangqiang Hu, Ming Fu, Jun Lv等完成。促进了肿瘤的精准治疗与个性化用药的发展，进一步强调了基因信息检测与分析的重要性。

肿瘤基因检测及靶向药物治疗研究关键词：

MM/GBSA,分子动力学模拟,非看门人突变,普拉塞替尼,休息。

肿瘤治疗检测基因临床应用结果

目的：RET（转染期间重排）激酶作为一种跨膜受体酪氨酸激酶，是非小细胞肺癌（NSCLC）和甲状腺癌等多种人类癌症的治疗靶点。 Pralsetinib 是最近批准用于治疗 RET 驱动的 NSCLC 和甲状腺癌的药物。 RET 激酶 C 叶的单点突变 G810C 导致 pralsetinib 对这种非看门人变体产生耐药性。然而，详细的机制仍然知之甚少。佳学基因解码的途径：在此，进行了多次微秒分子动力学（MD）模拟，分子力学/广义出生表面积（MM / GBSA）结合自由能计算和社区网络分析以揭示机制pralsetinib 对 RET G810C 突变体的耐药性。靶向药物研究的客观数据：模拟显示 G810C 突变对 RET 激酶结构域的整体构象动力学影响较小。能量分析表明 G810C 突变降低了 pralsetinib 与突变体的结合亲和力。每个残基的能量贡献和结构分析表明，pralsetinib 与铰链残基 Glu805 和 Ala807 之间的氢键相互作用在 G810C 突变体中被破坏，这导致 pralsetinib 与突变体的结合亲和力降低。药物指导及病因判断的依据：获得的结果可能提供对非网守 RET G810C 突变体 pralsetinib 耐药机制的理解。关键词：MM/GBSA；分子动力学模拟；非看门人突变；普拉塞替尼；休息。

肿瘤发生与革命国际数据库描述：

Objective: RET (rearranged during transfection) kinase, as a transmembrane receptor tyrosine kinase, is a therapeutic target for several human cancer such as non-small cell lung cancer (NSCLC) and thyroid cancer. Pralsetinib is a recently approved drug for the treatment of RET-driven NSCLC and thyroid cancers. A single point mutation G810C at the C-lobe of the RET kinase causes pralsetinib resistance to this non-gatekeeper variant. However, the detailed mechanism remains poorly understood.Methods: Here, multiple microsecond molecular dynamics (MD) simulations, molecular mechanics/generalized born surface area (MM/GBSA) binding free energy calculations, and community network analysis were performed to reveal the mechanism of pralsetinib resistance to the RET G810C mutant.Results: The simulations showed that the G810C mutation had a minor effect on the overall conformational dynamics of the RET kinase domain. Energetic analysis suggested that the G810C mutation reduced the binding affinity of pralsetinib to the mutant. Per-residue energy contribution and structural analyses revealed that the hydrogen bonding interactions between pralsetinib and the hinge residues Glu805 and Ala807 were disrupted in the G810C mutant, which were responsible for the decreased binding affinity of pralsetinib to the mutant.Conclusions: The obtained results may provide understanding of the mechanism of pralsetinib resistance to the non-gatekeeper RET G810C mutant.Keywords: MM/GBSA; Molecular dynamics simulations; Non-gatekeeper mutation; Pralsetinib; RET.

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