【佳學基因靶向藥物基因檢測】通過分子動力學模擬深入了解 pralsetinib 對非看門人 RET 激酶 G810C 突變的耐藥性

深圳品牌檢測基因費用香港

可知檢測結果分析中的基因解碼方法發(fā)現(xiàn)《J Mol Model》在?2022 Dec 28;29(1):24.發(fā)表了一篇題目為《》腫瘤靶向藥物治療基因檢測臨床研究文章。該研究由Shu Cao,?Changbin Tan,?Anhua Fei,?Gangqiang Hu,?Ming Fu,?Jun Lv等完成。促進了腫瘤的正確治療與個性化用藥的發(fā)展，進一步強調了基因信息檢測與分析的重要性。

腫瘤基因檢測及靶向藥物治療研究關鍵詞：

MM/GBSA,分子動力學模擬,非看門人突變,普拉塞替尼,休息。

腫瘤治療檢測基因臨床應用結果

目的：RET（轉染期間重排）激酶作為一種跨膜受體酪氨酸激酶，是非小細胞肺癌（NSCLC）和甲狀腺癌等多種人類癌癥的治療靶點。 Pralsetinib 是賊近批準用于治療 RET 驅動的 NSCLC 和甲狀腺癌的藥物。 RET 激酶 C 葉的單點突變 G810C 導致 pralsetinib 對這種非看門人變體產生耐藥性。然而，詳細的機制仍然知之甚少。佳學基因解碼的途徑：在此，進行了多次微秒分子動力學（MD）模擬，分子力學/廣義出生表面積（MM / GBSA）結合自由能計算和社區(qū)網絡分析以揭示機制pralsetinib 對 RET G810C 突變體的耐藥性。靶向藥物研究的客觀數據：模擬顯示 G810C 突變對 RET 激酶結構域的整體構象動力學影響較小。能量分析表明 G810C 突變降低了 pralsetinib 與突變體的結合親和力。每個殘基的能量貢獻和結構分析表明，pralsetinib 與鉸鏈殘基 Glu805 和 Ala807 之間的氫鍵相互作用在 G810C 突變體中被破壞，這導致 pralsetinib 與突變體的結合親和力降低。藥物指導及病因判斷的依據：獲得的結果可能提供對非網守 RET G810C 突變體 pralsetinib 耐藥機制的理解。關鍵詞：MM/GBSA；分子動力學模擬；非看門人突變；普拉塞替尼；休息。

腫瘤發(fā)生與革命國際數據庫描述：

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.