The role of reorganization energy in achieving selective kinase inhibition

重组能在实现选择性激酶抑制中的作用

• 批准号: 9216834
• 负责人: John Damon Chodera
• 金额: $ 33.74万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9216834
• 关键词: Accounting; Adverse effects; Affinity; Atlases; Binding; Binding Sites; Biological Assay; Biophysics; Case Study; Catalytic Domain; Cause of Death; Cessation of life; Chronic Myeloid Leukemia; Clinical; Complex; Crystallization; Data; Development; Diagnosis; Disease; Disseminated Malignant Neoplasm; Drug Design; Drug resistance; Effectiveness; Engineering; Event; FDA approved; Fluorescence; Free Energy; Generations; Health; Home environment; Human; Imatinib; Individual; Knowledge; Label; Ligands; Location; Malignant Neoplasms; Maps; Measures; Modeling; Molecular; Molecular Conformation; Mutation; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Play; Recombinants; Resistance development; Role; Route; Signal Pathway; Signal Transduction; Specificity; Structure; Therapeutic; Time; Toxic effect; Treatment Failure; Tyrosine Kinase Inhibitor; United States; Up-Regulation; Variant; Work; base; cancer therapy; cluster computing; cost; design; drug development; drug discovery; experimental study; inhibitor/antagonist; kinase inhibitor; mutant; novel; protein folding; resistance mutation; screening; simulation; small molecule; therapeutic development

PROJECT SUMMARY / ABSTRACT The ability to rationally design small molecules that bind with high affinity and specificity to one or more biomolecu- lar targets would radically transform drug discovery. Current approaches require many rounds of screening, mod- eling, and synthesis in a trial-and-error approach that is costly, time-consuming, and ineffective. After decades of work on the study of biomolecular interactions, there remains an enormous gulf between what we claim to un- derstand about biomolecular association and our ability to put this knowledge into practice. This gulf is especially wide for the design of selective kinase inhibitors, which aim to target one or more specific kinases in order to effectively treat a disease—often cancer—and minimize unwanted toxic side effects. While the discovery of imatinib was hailed as a breakthrough for its ability to selectively inhibit Abl despite the existence of closely related kinases like Src, it came as a great surprise when the crystal structure of imatinib bound to Src revealed that the Src:imatinib complex was nearly identical to Abl:imatinib. Recent evidence from both experiments and modeling has suggested that a previously underappreciated contribution—the energetic cost of populating the inhibitor-bound conformation—plays a critical role in the selectivity of imatinib for Abl over Src. While this effect has only been studied in the well-studied case of Abl/Src binding to imatinib, it has the potential to be much more general. We hypothesize that exploiting differences in the energetic cost of confining related kinases to inhibitor binding-competent conformations may be a route to selectivity in targeted kinase inhibition. Here, we ask how much conformational reorganization energy contributes to the affinity of current FDA-approved noncovalent kinase inhibitors to determine whether existing inhibitors exploit differences in these reorganization energies (perhaps inadvertently) to achieve selectivity, and whether there is a clear route to exploiting this difference in rationally engineering new selective molecules. We use a combined experimental and computational approach to decompose inhibitor binding affinity and se- lectivity into contributions from kinase reorganization and binding to individual kinase conformations. We first computationally map the conformations accessible to a diverse panel of human kinase catalytic domains, along with their associated energetics. By using an automated fluorescence assay to measure the affinities of FDA- approved noncovalent inhibitors to this panel and alchemical free energy calculations to determine the inhibitor binding affinities to individual conformations, we can combine these data to quantify the relative contribution of reorganization energy to the affinity and selectivity of kinase inhibition. We then use the introduction of point mutants intended to modulate selectivity via reorganization energies to validate our model, and examine oppor- tunities for exploiting differences in reorganization energy between related kinases or wild-type and mutationally activated kinases as a route to selectivity.

项目摘要 /摘要 合理设计的小分子的能力与高属性和特殊丘脑结合到一个或多个生物菌的能力 LAR靶标将从根本上改变药物发现。当前的方法需要多轮筛选，mod- Eling和综合方法是代价高昂，耗时且无效的方法。几十年后 在研究生物分子相互作用的研究中，我们声称没有 - 关于生物分子关联以及我们将这些知识付诸实践的能力的概念。这个海湾尤其是 宽阔的选择性激酶抑制剂的设计，旨在靶向一个或多个特定的激酶 有效治疗疾病（通常是癌症），并最大程度地减少不需要的毒性副作用。 虽然发现伊马替尼的发现是有选择地抑制ABL要求的能力的突破 诸如SRC之类的密切相关激酶的存在，当伊马替尼的晶体结构时，这真是一个惊喜 与SRC结合的揭示了SRC：伊马替尼复合物几乎与ABL：imatinib相同。最近的证据 实验和建模都表明，先前未被低估的贡献 - 能量 填充抑制剂结合构象的成本 - 弹奏伊马替尼对ABL的选择性的关键作用 src。尽管这种效果仅在abl/src与伊马替尼结合的良好的情况下进行了研究，但它具有 有可能变得更加笼统。我们假设利用了能量成本的差异 与抑制剂结合能力的考虑相关激酶可能是在选择性的途径 靶向激酶抑制。在这里，我们问多少构象重组能量有助于 当前FDA批准的非共价激酶抑制剂的依据，以确定现有抑制剂是否利用 这些重组能量的差异（也许是无意中的）以实现选择性，以及是否存在 在合理工程中开发这种差异的新途径新的选择性分子。 我们使用一种组合的实验和计算方法来分解抑制剂的结合功能和se- 从激酶重组和与个体激酶构象结合的贡献中进行讲座。我们第一次 在计算上绘制沿着人类激酶催化域的潜水面板访问的会议 与它们相关的能量学。通过使用自动荧光测定法测量FDA- 批准对该面板的非共价抑制剂和炼金术自由能计算，以确定抑制剂 将属性与个体构象结合，我们可以将这些数据结合起来，以量化 重组能量对激酶抑制作用的原则和选择性。然后，我们使用点的引入 突变体旨在通过重组能来调节选择性以验证我们的模型，而考生oppor- 隧道用于利用相关激酶或野生型和突变的重组能量差异 激活的激酶作为选择性的途径。