Core--Molecular Modeling

该计划项目的总体目标是放射性同位素载体分子和策略的翻译开发，以便为淋巴瘤和腺癌(如前列腺癌)提供全身放射治疗。第一个项目专注于开发新的合成高亲和力配体(SHALs)，它将针对人类白细胞抗原DRβ亚基的Lym-1表位，已知存在于几乎所有B细胞类型的恶性淋巴细胞上。第二个项目致力于开发新的双功能多价单链可变区(ScFv)单抗，用于前列腺癌的前靶向治疗，并随后开发一种90Y的小分子多价DOTA螯合剂。几种不同类型的分子建模已被用于支持这些项目。基于同源性的蛋白质结构预测被用来确定：1)人类白细胞抗原-DR 10的结构，2)单链抗体单抗靶向试剂，以及3)针对90Y DOTA螯合剂的单链抗体。这些预测的结构被用来帮助确定：1)Lym-1单抗表位，用于后续的计算对接研究；2)单链抗体与DOTA螯合剂的结合位点。用量子化学模拟和第一性原理分子动力学模拟预测了化学修饰对90Y-DOTA和DOTA-DOTA连接基结构的影响。最后，经典分子动力学被用于确定配体的结合方向、SHALS的设计、DOTA-DOTA连接物和聚乙二醇化的scFv支架的优化。这一核心组成部分为实现这些目标提供了计算模拟专门知识和设施。所有的模拟都是使用该小组已有的计算机硬件和软件进行的。我们 在生物学项目中拥有大量的计算机资源，并通过内部拨款在更大的机构计算机设施上投入大量的计算机时间。为这一核心挑选的研究人员在将采用的不同分子建模方法方面拥有丰富的经验。

The overall goal of this program project is the translational development of radioisotopic carrier molecules and strategies to deliver systemic radiotherapy for lymphomas and adenocarcinomas such as prostate cancer. The first project focuses on developing novel synthetic high affinity ligands (SHALs) that will target the Lym-1 epitope of the beta subunit of HLA-DR, known to be present on malignant lymphocytes of almost all B cell types. The second project focuses on developing novel bispecific multivalent single chain variable fragment (scFv) MAbs to be used to pretarget prostate cancer and to be followed by a small multivalent DOTA chelator of 90y. Several different types of molecular modeling has been used in support of the Projects. Homology-based protein structure prediction was used to determine: 1) the structures of HLA-DR 10, and 2) scFv MAb targeting agents, as well as 3) the scFv raised against the 90y DOTA chelator. These predicted structures were used to help identify: 1) the Lym-1 MAb epitope for subsequent computational docking studies and 2) scFv binding sites against the DOTA chelator. Quantum chemical simulations and first principles molecular dynamics simulations were used to predict the effects of chemical modifications on the structure of the 90Y-DOTA and the DOTA-DOTA linker. Finally, classical molecular dynamics were used to assist in determining the binding orientations of ligands, the design of SHALS, the optimization of the DOTA-DOTA linker and PEGylated scFv scaffold. This core component provided the computational simulation expertise and facilities to achieve these aims. All simulations were performed using computer hardware and software already available to the group. We have significant computer resources within the biology program, and extensive computer time on much larger institutional computer facilities through internal grants. The investigators selected for this Core have extensive experience in the different molecular modeling methods to be employed.