恢复B因子：对c-ros癌基因1受体酪氨酸激酶和间变性淋巴瘤激酶L1196M使用克唑替尼和劳拉替尼的回顾性标准化B因子分析
Reviving B-Factors: Retrospective Normalized B-Factor Analysis of c-ros Oncogene 1 Receptor Tyrosine Kinase and Anaplastic Lymphoma Kinase L1196M with Crizotinib and Lorlatinib.
作者信息
Johnson Ted W, Gallego Rebecca A, Brooun Alexei, Gehlhaar Dan, McTigue Michele
机构信息
Oncology Medicinal Sciences, Pfizer Inc., 10770 Science Center Drive, San Diego, California 92121, United States.
出版信息
ACS Med Chem Lett. 2018 Jun 18;9(9):878-883. doi: 10.1021/acsmedchemlett.8b00147. eCollection 2018 Sep 13.
Abstract
Structure-based drug design (SBDD) is commonly leveraged in rational drug design. Usually, ligand and binding site atomic coordinates from crystallographic data are exploited to optimize potency and selectivity. In addition to traditional, static views of proteins and ligands, we propose using normalized B-factors to study protein dynamics as a part of the drug optimization process. A retrospective case study of crizotinib and lorlatinib bound to both c-ros oncogene 1 kinase (ROS1) and anaplastic lymphoma kinase (ALK) L1196M related normalized B-factors to differences in binding affinity. This analysis showed that ligand binding can have protein-stabilizing effects that start near the ligand but propagate through nearby residues and structural waters to more distal motifs. The potential opportunities for analyzing normalized B-factors in SBDD are also discussed.
摘要
基于结构的药物设计（SBDD）常用于合理药物设计中。通常，利用晶体学数据中的配体和结合位点原子坐标来优化效力和选择性。除了传统的蛋白质和配体静态视图外，我们建议在药物优化过程中使用归一化B因子来研究蛋白质动力学。对克唑替尼和劳拉替尼与c-ros癌基因1激酶（ROS1）和间变性淋巴瘤激酶（ALK）L1196M结合的回顾性案例研究，将相关归一化B因子与结合亲和力差异联系起来。该分析表明，配体结合可产生蛋白质稳定作用，这种作用始于配体附近，但会通过附近的残基和结构水传播到更远端的基序。还讨论了在基于结构的药物设计中分析归一化B因子的潜在机会。
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