Core--Molecular Modeling

该项目的总体目标是转化开发放射性同位素载体分子和策略，为淋巴瘤和腺癌（如前列腺癌）提供全身放射治疗。第一个项目侧重于开发新的合成高亲和力配体（SHALs），该配体将靶向HLA-DR β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。第二个项目的重点是开发新的双特异性多价单链可变片段（scFv）单克隆抗体，用于前列腺癌的预靶向，并随后开发一种90y的小多价DOTA螯合剂。几种不同类型的分子建模已被用于支持项目。基于同源性的蛋白结构预测用于确定：1)hla - dr10的结构，2)scFv MAb靶向剂的结构，以及3)针对90y DOTA螯合剂的scFv。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)针对DOTA螯合剂的scFv结合位点。利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连接体结构的影响。最后，利用经典分子动力学方法确定了配体的结合方向，设计了SHALS，优化了DOTA-DOTA连接体和聚乙二醇化scFv支架。这个核心组件提供了实现这些目标的计算模拟专业知识和设施。所有的模拟都是使用小组现有的计算机硬件和软件进行的。我们

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.