A Water-Based Mechanism of Specificity and Resistance for Lapatinib with ErbB Family Kinases
A Water-Based Mechanism of Specificity and Resistance for Lapatinib with ErbB Family Kinases
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DOI：
10.1021/bi2016553
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发表时间：
2012-03-27
期刊：
影响因子：
2.9
通讯作者：
Rizzo, Robert C.
中科院分区：
文献类型：
--
作者：
Huang, Yulin;Rizzo, Robert C.
双激酶抑制剂拉帕替尼对 EGFR 和 HER2 具有高亲和力，但对 ErbB4 具有弱亲和力，尽管驱动受体酪氨酸激酶 ErbB 家族的这些高度同源成员的特异性的因素尚不清楚。在本报告中，采用同源建模、分子动力学模拟和自由能计算，旨在揭示拉帕替尼特异性和耐药性的能量和结构分子基础。结果揭示了三个结合位点水分子的独特网络，与 ErbB4 相比，EGFR 和 HER2 产生了惊人相似的水合模式，而 ErbB4 显示出不同的模式，其中一个位置的占用率减少。主要原因可追溯到结合位点（EGFR 位置 775）的单个氨基酸变化，涉及从 C 或 S（EGFR 和 HER2）到 V（ErbB4）的交换，其侧链更大、疏水，并且缺乏与水形成氢键的能力。值得注意的是，当计算中包含关键水域时，整个系列 (EGFR > HER2 > ErbB4) 与实验活动获得了极好的定量一致性。从数量上讲，网络水域和网络中涉及的物种之间的库仑相互作用和氢键计数在 ErbB4 中不如 EGFR 或 HER2 中的情况低约 40%。对临床相关 EGFR（C775F、T854A 和 T790M）和 HER2 (T790I) 突变体的其他模拟表明，耐药性也可以通过结合位点水网络中发生的变化来理解。总体而言，这项研究的结果产生了一种物理上合理的水基机制，用于描述拉帕替尼的特异性和耐药性。
The dual kinase inhibitor lapatinib has a high affinity for EGFR and HER2 but a weak affinity for ErbB4, although the factors driving specificity for these highly homologous members of the ErbB family of receptor tyrosine kinases are not well understood. In this report, homology modeling, molecular dynamics simulations, and free energy calculations are employed with the goal of uncovering the energetic and structural molecular basis of lapatinib specificity and resistance. The results reveal a distinct network of three binding site water molecules that yield strikingly similar hydration patterns for EGFR and HER2 in contrast to that of ErbB4, which shows a different pattern with a reduced occupancy at one of the positions. The primary cause was traced to a single amino acid change in the binding site (EGFR position 775), involving a swap from C or S (EGFR and HER2) to V (ErbB4), for which the side chain is bulkier, is hydrophobic, and lacks the ability to form a H-bond with water. Notably, excellent quantitative agreement with experimental activities is obtained across the series (EGFR > HER2 > ErbB4) when key waters are included in the calculations. Quantitatively, Coulombic interactions and H-bond counts between network waters and species involved in the network are less favorable in ErbB4 by similar to 40% relative to those in EGFR or HER2. Additional simulations with clinically relevant EGFR (C775F, T854A, and T790M) and HER2 (T790I) mutants demonstrate that resistance can also be understood in terms of changes that occur in the binding site water network. Overall, the results of this study have yielded a physically reasonable water-based mechanism for describing lapatinib specificity and resistance.