Molecular Modeling in Metal Based Imaging Agent Design

超出所提供的空间。 在这个建议中，我们寻求扩大我们最初资助的申请中开始的工作（大卫E。Reichert，P.I. 8 R 01 EB 00340）关于在基于金属的成像剂的设计中使用分子建模。基于结构设计的有效工具的存在将极大地帮助基于金属的成像剂的开发。为了开发这样的工具，我们寻求开发用于预测基于放射性金属的成像剂与两种血清转运蛋白（人血清白蛋白和性激素结合球蛋白）以及与雌激素受体的结合亲和力的方法。我们实现这一目标的具体目标如下：1.在二氧化硅中开发基于反式二取代的cyclen和cyclam骨架的Cu（II）配体库。 2.将我们的筛选文库对接到人血清白蛋白（HSA）、性激素结合球蛋白（SHBG）和两种雌激素受体亚型（ER α和ER 3）的结合位点。使用MM-PBSA方法计算每种研究蛋白质中复合物子集的结合自由能。 4.实验合成相同的分子子集，并使用平衡透析测量与每种研究蛋白质的结合亲和力。 5.使用计算的自由能和对接的姿势，开发用于预测测量的结合亲和力的评分函数。 6.开发一套基于网络的工具，使其他研究人员能够直接利用我们当前和未来的QSAR模型预测他们自己化合物的生物学行为。 当受体的分子结构已知时，分子对接已经成为药物设计中的一个有价值的工具;随着对接程序和计算机硬件的进步，现在可以进行虚拟筛选研究。这些相同的技术也可以应用于基于金属的成像剂的开发;主要问题是缺乏大量此类化合物的实验数据。在这项建议中，我们试图开发这样的数据，并开发和验证区分良好的中度结合放射性金属络合物的方法。性能现场=

EXCEED THE SPACE PROVIDED. In this proposal we seek to expand on work begun in our original funded application (David E. Reichert, P.I. 8 R01 EB00340) on the use of molecular modeling in the design of metal based imaging agents. The development of metal based imaging agents would be greatly aided by the existence of well validated tools for structure-based design. In order to develop such tools we seek to develop methods for predicting the binding affinities of radiometal based imaging agents to two serum transport proteins, human serum albumin, and sex hormone binding globulin, and to the estrogen receptor. Our specific aims to accomplish this goal are as follows: 1. Develop in silica a library of Cu(II) ligands, based on trans-disubstituted cyclen and cyclam backbones. 2. Dock our screening libraries into the binding sites of human serum albumin (HSA), sex hormone binding globulin (SHBG), and two isoforms of the estrogen receptor (ER a andER 3. Calculate the free energies of binding using the MM-PBSA methodology for subsets of the complexes in each of the studied proteins. 4. Experimentally synthesize the same subsets of molecules and measure the binding affinities to each studied protein using equilibrium dialysis. 5. Develop scoring functions for predicting the measured binding affinities, using both the calculated free energies and docked poses. 6. Develop a set of web based tools for other researchers to be able to directly utilize our current and future QSAR models predicting biological behavior on their own compounds. Molecular docking has become a valuable tool in drug design when the molecular structure of the receptor is known; with advances in docking programs and computer hardware it is now possible to perform virtual screening studies. These same techniques could be applied to the development of metal based imaging agents as well; a major problem is the paucity of experimental data for large sets of such compounds. In this proposal we seek to develop such data and to develop and validate methods for distinguishing good from moderate binding radiometal complexes. PERFORMANCE SITE ========================================Section End===========================================