Structural Biology Core

《结构生物学与生物物理核心》项目总结 结构生物学和生物物理学(SBB)核心的目标是帮助实现ADDD中心的总体目标 开发用于阿尔茨海默病(AD)新靶点的高质量先导化合物(总体里程碑3)。 SBB核心将与其他技术核心合作，为HIT提供计算机辅助药物设计 生成和优化、用于结构指导设计的共结晶以及目标结构信息 目标支持包(TEP)。SBB核心将能够在第一时间识别HIT分子 用X射线衍射法或冷冻电子法阐明优先ADDD中心靶的未知结构 显微镜，然后利用这些结构(或已知的已发表结构)来执行计算机辅助 通过多种电子计算机方法进行药物设计。优先考虑的分子将由MCCB核心和 在目标特定的体外分析流程方案(ADHTS Core)中进行评估，以完成迭代周期。为了进一步 辅助结构活性关系分析和Hit-to-Lead优化过程，蛋白质共晶体 目标和新设计的小分子结合剂将被生长和衍射。这些数据将用于 结构导向设计，以优化配体和蛋白质结合位点之间的相互作用。通过 SBB核心的贡献，ADDD中心的科学家将在优化HITS方面取得快速进展 通过计算模拟和有助于建立连接性的结构研究来引导分子 分子设计和生物功能之间的关系。 SBB Core由Andrew Mesecar博士和Markus Lill博士领导，他们负责 核心、结晶学/结构测定和计算机辅助药物设计。这个 SBB核心的组成将主要由研究生和博士后学生组成。此外，工作人员 来自普渡大学广泛的核心设施，包括大分子结晶学和冷冻电子 显微镜设施，将支持SBB的核心活动。 SBB核心的具体目标是： 具体目标1：确定基于结构的设计-服从提名目标。 具体目标2：阐明靶标结构以指导药物发现活动。 具体目标3：预测和设计潜在的HIT分子结构，用于迭代分子设计， 综合和测试。

PROJECT SUMMARY Structural Biology & Biophysics Core The goal of the Structural Biology & Biophysics (SBB) Core is to help achieve the overall ADDD CENTER aim of developing high quality lead compounds for novel Alzheimer's Disease (AD) targets (Overall MILESTONE 3). The SBB Core will work in concert with the other Technical Cores to provide computer aided drug design for hit generation and optimization, co-crystallization for structure guided design, and target structural information for Target Enablement Packages (TEPs). The SBB Core will enable the identification of hit molecules by first elucidating unknown structures for prioritized ADDD CENTER targets via x-ray diffraction or cryo-electron microscopy, then utilizing those structures (or already known published structures) to perform computer aided drug design via multiple in silico methods. Prioritized molecules will be synthesized by the MCCB Core and evaluated in target specific in vitro assay flow schemes (ADHTS Core) to complete the iteration cycle. To further aid in the structure activity relationship analysis and hit-to-lead optimization process, co-crystals of the protein target and newly designed small molecule binders will be grown and diffracted. The data will be utilized for structure guided design to optimize interactions between the ligand and protein binding sites. Through the contributions of the SBB Core, rapid progress will be made by ADDD CENTER scientists in optimizing hits into lead molecules through both computational simulations and structural studies that help establish connectivity between molecular design and biological function. The SBB Core is led by Drs. Andrew Mesecar and Markus Lill who are responsible for the two components of the core, crystallography/structure determination and computer aided drug design, respectively. The composition of the SBB Core will primarily consist of graduate and post-doctoral students. Additionally, staff from Purdue's extensive core facilities, including the Macromolecular crystallography and cryo-electron microscopy facility, will support SBB Core activities. The Specific Aims of the SBB Core are: Specific Aim 1: Identification of structure based design-amenable nominated targets. Specific Aim 2: Elucidate target structures to guide drug discovery activities. Specific Aim 3: Predict and design potential hit molecular structures for iterative molecular design, synthesis, and testing.