Solvation Directed Design of Flavonoid Derivatives for Caspase Inhibition

描述（由申请人提供）：该项目旨在开发一种合理的设计方法，该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，使其以更大的亲和力与给定的靶标结合。该方法将被应用于设计类黄酮化合物的修饰，使所得的类似物特异性和强烈抑制蛋白质的Caspase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的化学势的近似三维映射。这种方法解决了两个众所周知的缺陷，在大多数计算方法，旨在预测配体结合亲和力。首先，在保持计算效率的同时，它捕获了大多数旨在预测配体-蛋白质结合亲和力的方法忽略的水溶剂化的基本分子长度尺度物理学。第二，它提供了具体的信息和物理见解，如何铅药物应修改，如产生衍生物，可以结合更大的亲和力和特异性，以给定的目标 由于这些功能，WaterMap方法在潜在客户优化过程中显示出很大的帮助前景。类黄酮类似物的合理设计，更具体和更强的抑制剂的蛋白质的半胱天冬酶家族将作为一个测试案例，长期目标是开发一种方法，适用于所有水合蛋白质的目标。具体目标1旨在设计和实施一种合理的设计方法，该方法结合了WaterMap技术提供的溶剂化信息，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的评估将是具体目标2的目标，具体目标2是应用新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。 公共卫生相关性：这项工作与公共卫生高度相关，因为它将提高我们合理设计更有效、副作用更少的药物的能力。

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. PUBLIC HEALTH RELEVANCE: This work is highly relevant to public health since it will improve our capability to rationally design more potent drugs with fewer side effects.