Understanding, Predicting, and Engineering Membrane Permeability

了解、预测和工程膜渗透性

• 批准号: 7762177
• 负责人: MATTHEW P JACOBSON
• 金额: $ 25.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762177
• 关键词: Africa; African Trypanosomiasis; Biological Availability; Biological Models; Biology; Cell Membrane Permeability; Cells; Chemicals; Collaborations; Computer Simulation; Computing Methodologies; Coupling; Cyclic Peptides; Cysteine Protease; Data; Development; Diffusion; Elements; Encapsulated; Engineering; Environment; Generations; Goals; Hydrogen Bonding; Hydrophobicity; Joints; Knowledge; Lead; Literature; Membrane; Methods; Modeling; Muscle Rigidity; Paper; Parasites; Parasitic Diseases; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Physics; Preparation; Property; Proteins; Publications; Relative (related person); Role; Series; Staging; Test Result; Testing; Time; Work; base; chemical property; computer program; cost; design; drug candidate; drug discovery; flexibility; improved; inhibitor/antagonist; membrane model; public health relevance; small molecule; stereochemistry; success; tool

DESCRIPTION (provided by applicant): The ability of small molecules to enter cells is a critical parameter in development of pharmaceutical agents and tools for chemical biology. Most synthetic compounds enter cells by passive diffusion across the membrane. The goal of this proposal is to increase our understanding of, and ability to predict, passive membrane permeation. The ultimate test of this understanding will be rationally modifying compounds to improve membrane permeation. The work proposed here builds on existing models of membrane permeation, but the model we are developing differs from most in practical use by being more directly based on an understanding of the physics of passive membrane permeation. As such, it is systematically improvable, and has broad applicability. We propose to 1. Implement and test a physics-based model for passive membrane permeability. A first generation of this model has been described in a series of papers by the PI, and has emphasized the role of conformational flexibility and the ability to form internal hydrogen bonds in promoting membrane permeation. We will extend this model to include other critical aspects of the physics, including entropic losses upon membrane insertion and the semi-ordered hydrophobic environment of the membrane interior, comparing to both literature data and new data generated in Aims 2 and 3. 2. Interrogate key aspects of membrane permeation using cyclic peptides, and use this knowledge to design highly permeable cyclic peptides. We propose to use cyclic peptides as a challenging model system for studying passive membrane permeation. The relative synthetic ease of creating cyclic peptides facilitates developing series of compounds that differ in well-defined ways, such as stereochemistry, rigidity, size, hydrophobicity, etc. As in our earlier work, computational predictions will always be made prior to experimental testing, and the results will probe specific aspects of the physics of membrane permeation. 3. Interrogate key aspects of membrane permeation using non-peptidic small molecules, and use this knowledge in practical efforts to optimize the chemical properties of protein inhibitors. One of the collaborative projects involves improving membrane permeability for inhibitors of parasite cysteine proteases, which have typically had poor bioavailability. A central element of this proposal is collaborations with chemists Scott Lokey (UCSC) and Adam Renslo (UCSF) to test and apply the computational models. Tight coupling between computational modeling and experimental testing is central to this proposal, allowing iterative improvement of our physical understanding of passive membrane permeability and computational methods that encapsulate that understanding. Success of this work will enable hypothesis-driven ("engineering") approaches to improving membrane permeability. PUBLIC HEALTH RELEVANCE: One important property of drugs is their ability to enter cells, especially for drugs that are taken orally. This proposal is concerned with developing new computer programs that can predict the ability of compounds to enter cells, and experimental testing of these methods. Success of this work has the potential to reduce the time and cost of early-stage drug discovery, such as the proposed project to develop improved drug candidates for "sleeping sickness", a serious parasitic disease common in Africa.

描述（由申请方提供）：小分子进入细胞的能力是开发化学生物学药剂和工具的关键参数。大多数合成化合物通过被动扩散穿过细胞膜进入细胞。该提案的目的是增加我们对被动膜渗透的理解和预测能力。这种理解的最终测试将是合理地修改化合物以改善膜渗透。这里提出的工作建立在现有的膜渗透模型，但我们正在开发的模型不同于大多数在实际使用中，更直接地基于被动膜渗透的物理学的理解。因此，它是可系统改进的，并且具有广泛的适用性。我们建议1。实施并测试被动膜渗透性的物理模型。PI在一系列论文中描述了该模型的第一代，并强调了构象灵活性和形成内部氢键的能力在促进膜渗透中的作用。我们将扩展该模型，以包括物理学的其他关键方面，包括膜插入时的熵损失和膜内部的半有序疏水环境，与文献数据和目标2和3中生成的新数据进行比较。2.使用环肽探究膜渗透的关键方面，并使用这些知识设计高渗透性的环肽。我们建议使用环肽作为一个具有挑战性的模型系统，研究被动膜渗透。相对合成容易创建环肽有利于开发一系列的化合物，不同的定义明确的方式，如立体化学，刚性，大小，疏水性等，在我们早期的工作，计算预测将始终在实验测试之前，结果将探测膜渗透的物理学的具体方面。3.使用非肽类小分子探究膜渗透的关键方面，并在实际工作中使用这些知识来优化蛋白质抑制剂的化学性质。其中一个合作项目涉及改善寄生虫半胱氨酸蛋白酶抑制剂的膜渗透性，这种抑制剂通常生物利用度很差。该提案的一个核心要素是与化学家Scott Lokey（UCSC）和Adam Renaissance（UCSF）合作，以测试和应用计算模型。计算建模和实验测试之间的紧密耦合是这个建议的核心，允许迭代改进我们对被动膜渗透性的物理理解和封装这种理解的计算方法。这项工作的成功将使假设驱动（“工程”）的方法，以提高膜渗透性。 公共卫生相关性：药物的一个重要特性是它们能够进入细胞，特别是口服药物。该提案涉及开发新的计算机程序，可以预测化合物进入细胞的能力，并对这些方法进行实验测试。这项工作的成功有可能减少早期药物发现的时间和费用，例如拟议的开发“昏睡病”候选药物的项目，昏睡病是非洲常见的一种严重寄生虫病。