Solvation Directed Design of Flavonoid Derivatives for Caspase Inhibition

用于抑制 Caspase 的类黄酮衍生物的溶剂化定向设计

基本信息

批准号：
8458118
负责人：
Thomas Philip Kurtzman
金额：
$ 11.01万
依托单位：
HERBERT H. LEHMAN COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-10 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8458118
关键词：
3-Dimensional Active Sites Address Adult Adverse effects Affinity American Area Binding Binding Proteins Biological Assay Caspase Caspase Inhibitor Charge Chemicals Collaborations Computational Technique Computing Methodologies Development Drug Industry Drug Prescriptions Effectiveness FDA approved Flavonoids Goals Head Health Benefit Kinetics Lead Length Ligand Binding Ligands Maps Marketing Mechanics Methodology Methods Modification Molecular Molecular Biology Organic Chemistry Outcome Pharmaceutical Preparations Physics Play Price Process Property Protein Family Proteins Public Health Research Role Route Running Shapes Specificity Techniques Technology Testing Theoretical Studies Thermodynamics Validation Water Work analog base combinatorial computer studies cost design improved insight interest meetings member molecular dynamics molecular recognition process optimization professor programs tool

项目摘要

DESCRIPTION (provided by applicant): This project seeks to develop a rational design methodology that utilizes a powerful solvation analysis tool, WaterMap, to direct the modification of lead compounds so that they bind with greater affinity to a given target. The methodology will be applied to design modifications to flavonoid compounds so that the resulting analogues specifically and strongly inhibit members of the Caspase family of proteins. The WaterMap technology utilizes explicit molecular dynamics simulations and a rigorous statistical mechanical theoretical treatment to create an approximate 3-dimensional mapping of the chemical potential of solvation of protein active sites. This methodology addresses two well-known deficiencies in most computational methods aimed at predicting ligand-binding affinity. First, while maintaining computational efficiency, it captures essential molecular length scale physics of water solvation that most methodologies aimed at predicting ligand-protein binding affinities ignore. Second, it provides specific information and physical insight into how lead-drugs should be modified such as to produce derivatives that can bind with greater affinity and with specificity to given targets Because of these features, the WaterMap methodology shows great promise as an aid in the lead optimization process. The rational design of flavonoid analogues that are more specific and stronger inhibitors of the caspase family of proteins will serve as a test case with the long term goal of developing a methodology that is applicable to all hydrated protein targets. Specific Aim 1 seeks to design and implement a rational design methodology that incorporates solvation information provided by the WaterMap technology that is capable of directing the design of modifications to lead compounds such that they bind with higher affinity to given targets. The assessment of Specific Aim 1 will be the goal of Specific Aim 2 which is to apply the new methodology to design modifications to flavonoid compounds that result in flavonoid analogues that bind with greater affinity to members of the Caspase family of proteins.

描述（由申请人提供）：该项目旨在开发一种合理的设计方法，利用强大的溶剂化分析工具 WaterMap 来指导先导化合物的修饰，以便它们以更大的亲和力与给定的靶标结合。该方法将应用于黄酮类化合物的设计修饰，以便所得类似物特异性且强烈地抑制 Caspase 蛋白家族的成员。 WaterMap 技术利用明确的分子动力学模拟和严格的统计力学理论处理来创建蛋白质活性位点溶剂化化学势的近似 3 维映射。该方法解决了大多数旨在预测配体结合亲和力的计算方法中的两个众所周知的缺陷。首先，在保持计算效率的同时，它捕获了水溶剂化的基本分子长度尺度物理学，而大多数旨在预测配体-蛋白质结合亲和力的方法都忽略了这一点。其次，它提供了关于如何修饰先导药物的具体信息和物理见解，例如生产可以以更大的亲和力和特异性结合给定靶点的衍生物由于这些功能，WaterMap 方法显示出作为先导化合物优化过程的辅助手段的巨大前景。类黄酮类似物是更特异、更强的半胱天冬酶家族蛋白抑制剂，其合理设计将作为一个测试案例，其长期目标是开发一种适用于所有水合蛋白靶标的方法。具体目标 1 寻求设计和实施合理的设计方法，该方法结合了 WaterMap 技术提供的溶剂化信息，该技术能够指导先导化合物的修饰设计，使其以更高的亲和力与给定靶标结合。具体目标 1 的评估将成为具体目标 2 的目标，具体目标 2 是应用新的方法来设计对类黄酮化合物的修饰，从而产生与 Caspase 蛋白家族成员具有更大亲和力的类黄酮类似物。