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Theory and Modeling of Noncovalent Binding

非共价结合的理论和建模

基本信息

批准号：
10471030
负责人：
MICHAEL K. GILSON
金额：
$ 5.78万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471030
关键词：
Affinity Binding Binding Proteins Binding Sites Biological Models Calorimetry Chemicals Clinical Trials Computer software Computing Methodologies Consumption Cyclodextrins Data Disease Docking Drug Delivery Systems Drug Design Drug Formulations Error Sources Free Energy Goals Grant Libraries Ligand Binding Ligands Liquid substance Measures Methods Modeling Molecular Weight Pharmaceutical Preparations Pharmacologic Substance Phase Physics Property Protein Engineering Proteins Science Scientist Solvents Speed Structure System Testing Time Uncertainty Water Work aqueous base chemical group cost design drug discovery enthalpy improved information model molecular dynamics molecular recognition novel novel strategies protonation quantum receptor screening simulation small molecule success theories trustworthiness virtual virtual screening

项目摘要

Project Summary Identifying a small molecule that tightly binds a targeted protein is a time-consuming, costly step in many drug discovery projects. Explicit solvent free energy methods can be used to predict small molecule-protein binding affinities and thus assist with this step. However, they do not provide consistently accurate predictions, and limitations in the force fields they use are implicated as a key source of error. Our main goal, therefore, is to help generate more trustworthy force fields. In particular, we aim to prove principle for the use of experimental binding data for host-guest systems, along with traditionally used liquid properties, to refine force field parameters. We also aim show that free energy methods can help predict ligand binding poses and rank compound libraries against targeted proteins. First, we will expand the chemical diversity of host-guest systems, by developing facile methods of derivatizing cyclodextrin host molecules, and using these methods to create new, water- soluble cyclodextrin derivatives. We will measure their binding free energies and enthalpies with varied guest molecules, and will use these new data to test and refine force fields. We also aim to prove principle for the use of sensitivity analysis to refine Lennard-Jones (LJ) parameters in existing atom-typed force fields, based on host-guest binding data and liquid property data. In addition to adjusting existing atom-typed parameters, we will develop an atoms-in-molecules approach to mapping a quantum calculation for a molecule to LJ parameters for that molecule. By reducing the number of parameters, relative to atom-typed methods, this approach should enable global parameter optimization, rather than just refinement of existing parameters. Finally, we will automate and optimize our lab’s attach-pull-release (APR) method of computing binding free energies so that it can be used to rank candidate poses of a ligand in a binding site; the most stable few poses will then be used for full binding free energy calculations. Success in this effort will enable free energy methods to be used in virtual compound screening. In addition, we will use the APR method to test the new parameters generated above in the context of protein-ligand binding.

项目概要识别与目标蛋白质紧密结合的小分子是一个耗时且昂贵的步骤在许多药物发现项目中。显式无溶剂能量方法可用于预测小分子-蛋白质结合亲和力，从而有助于此步骤。然而，他们并不提供一致准确的预测，并且他们使用的力场的局限性是被认为是错误的关键来源。因此，我们的主要目标是帮助产生更多值得信赖的力场。特别是，我们的目标是证明使用实验的原理结合主客体系统的数据以及传统上使用的液体特性，以改进力场参数。我们还旨在证明自由能方法可以帮助预测配体针对目标蛋白质的结合姿势和化合物库排序。首先，我们将通过开发简便的方法来扩大主客体系统的化学多样性衍生化环糊精主体分子，并使用这些方法创造新的、水- 可溶性环糊精衍生物。我们将测量它们的结合自由能和焓不同的客体分子，并将使用这些新数据来测试和完善力场。我们还旨在证明使用敏感性分析来改进 Lennard-Jones (LJ) 的原理现有原子型力场中的参数，基于主客体结合数据和液体财产数据。除了调整现有的原子类型参数外，我们还将开发一个将分子的量子计算映射到 LJ 的分子中原子方法该分子的参数。通过减少参数数量，相对于原子类型方法，这种方法应该能够实现全局参数优化，而不仅仅是细化现有参数。最后，我们将自动化和优化我们实验室的附加-拉动-释放（APR）计算方法结合自由能，以便它可用于对结合位点中配体的候选姿势进行排序；然后，最稳定的几个姿势将用于完全结合自由能计算。成功于这项工作将使自由能方法能够用于虚拟化合物筛选。在另外，我们将使用APR方法来测试上面生成的新参数蛋白质-配体结合的背景。

项目成果

期刊论文数量（98）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The temperature-dependence of host-guest binding thermodynamics: experimental and simulation studies.

DOI：
10.1039/d3sc01975f
发表时间：
2023-11-01
期刊：
CHEMICAL SCIENCE
影响因子：
8.4
作者：
Grimm, Laura M.;Setiadi, Jeffry;Tkachenko, Boryslav;Schreiner, Peter R.;Gilson, Michael K.;Biedermann, Frank
通讯作者：
Biedermann, Frank

Overcoming dissipation in the calculation of standard binding free energies by ligand extraction.