Public/Private Collaboration for High-Quality Protein-Ligand Data

描述(由申请人提供)：开发可靠的对接和评分(d/S)的一个关键需求是包含高质量的实验蛋白质-配体复杂结构的大型数据集，以及准确的结合亲和力数据。将利用私人投资司在这一领域的广泛专门知识，并通过社区参与，创建一个在线D/S资源(D/S资源)。SA1将建立最大的、可自由访问的蛋白质-配体复合体数据库，其结合亲和力是通过实验从文献中确定的。这个新的资源将建立在现有的两个最大的蛋白质配体数据集的基础上：Wang的PDBind和Carlson的结合MOAD。SA2将产生新的实验数据。另一个主要障碍是不同研究小组产生的结合亲和力数据与使用不同实验技术/条件的数据之间缺乏一致性。为了解决这一不足，将使用两种互补技术：等温量热法和表面等离子体共振技术来确定选定的蛋白质-配体复合体的解离常数(KDS)。此外，还将确定配体的重要物理化学性质(logP/logD、pKA和溶解度)，并解决其他晶体结构。SA3将整理来自社区的数据。大型数据集的沉积将要求制药公司、美国国立卫生研究院和学术界进行。这一目标包括解决存放在d/s资源中的部分完成的晶体结构，以及分析存放的数据以确定配体和蛋白质的多样性/相似性，以便优先在SA2中进行进一步的实验研究。SA4概述了拟议的社区外展计划。D/s资源将不会是密歇根州唯一的努力。数据将存储在许多存储库中：结构存储到PDB中，ITC数据存储到BindingDB中，以及化学信息存储到PubChem和NIST数据库中。将寻求与其他组织的合作。将为S举办竞赛和会议，并将设立访问学者计划，以鼓励新的发展，促进资源共享。 该项目将提供一个独特的资源，需要改进基于结构的药物设计领域。更好的技术将在开发新疗法方面节省时间和金钱，最终以更快的速度和更低的成本向更多的人口提供新药。

DESCRIPTION (provided by applicant): One critical need for the development of reliable docking and scoring (d/s) is a large dataset containing high quality experimental protein-ligand complex structures, together with accurate binding affinity data. An online d/s resource (d/sResource) will be created by taking advantage of the PIs extensive expertise in this area and through community participation. SA1 will build the largest, freely accessible database of protein-ligand complexes with experimentally determined binding affinities from literature. This new resource will build off of the two largest protein-ligand datasets in existence: Wang's PDBbind and Carlson's Binding MOAD. SA2 will generate new experimental data. The lack of consistency between binding affinity data generated from different research groups and using different experimental techniques/conditions is another major hurdle. To address this deficiency, dissociation constants (Kds) for selected protein-ligand complexes will be determined using two complementary techniques: isothermal calorimetry and surface plasmon resonance. Furthermore, important physicochemical properties for the ligands will be determined (logP/logD, pKa, and solubility), and additional crystal structures will be solved. SA3 will curate data from the community. Deposition of large datasets will be requested from pharma, the NIH, and academia. This Aim includes solving partially completed crystal structures deposited into the d/sResource and analysis of deposited data for diversity/similarity across the ligands and proteins to prioritize for further experimental investigation in SA2. SA4 outlines the proposed community outreach. The d/sResource will not be a Michigan-only endeavor. Data will be deposited in many repositories: structures into the PDB, ITC data into BindingDB, and chemical information into Pubchem and NIST databases. Collaborations will be sought with other groups. Contests and meetings for d/s will be held, and a Visiting Scholars Program will be established to encourage new developments and facilitate the sharing of resources. The project will provide a unique resource that is needed to improve in the field of structure-based drug design. Better techniques will save time and money in the development of new treatments, ultimately providing new drugs more quickly and at less expense to the greater population.