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，使它们与给定目标具有更大的亲和力。该方法将应用于设计类黄酮化合物的修饰，使所得到的类似物特异性和强烈地抑制Caspase家族蛋白的成员。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三维映射。这种方法解决了大多数用于预测配体结合亲和力的计算方法中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，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，它提供了具体的信息和物理见解，如何修改铅药物，如生产衍生物，可以结合更大的亲和力和特异性给定的目标

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.