Ultra-large library docking for ligand discovery

用于配体发现的超大文库对接

• 批准号: 10023266
• 负责人: John J. Irwin
• 金额: $ 38.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-27 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023266
• 关键词: 3-Dimensional; Affinity; Agonist; Binding Sites; Biological; Biology; Charge; Chemicals; Communities; Computers; Crystallography; DNA; Databases; Docking; Dopamine; Dopamine Receptor; Ensure; G-Protein-Coupled Receptors; Growth; Hydrophobicity; Individual; Infrastructure; Joints; Lead; Letters; Libraries; Ligands; Measures; Methods; Molecular; Morphologic artifacts; Opioid; Outcome; Planets; Reaction; Resort; Testing; Work; base; chemical synthesis; combinatorial chemistry; computing resources; conformer; cost; innovation; interest; kappa opioid receptors; novel; receptor; scaffold; small molecule; success; three dimensional structure; tool; virtual library

PROJECT SUMMARY / ABSTRACT Despite much interest in expanding chemical space, diverse, billion molecule libraries remain inaccessible. In principle, docking a virtual library could access some of this missing chemical space. This idea has until now been vitiated by two key problems: 1. prediction of readily synthesized molecules has been challenging, without resorting to strategies that collapse diversity; and 2. docking is notoriously inaccurate. Two recent advances have made virtual library docking screens seem less fanciful. First, our collaborators at Enamine, a widely used fine chemicals supplier, have defined a 0.7 billion molecule make-on-demand library based on >100 reactions that they have under good control; >650,000 of these have been successfully synthesized. Second, while docking retains serious errors, it has made pragmatic progress, and has found genuinely novel ligands for >100 targets. The specific aims are: Aim 1. A robust, searchable, and dockable database of 3 billion diverse lead-like molecules. We will A. Enumerate 3 billion vetted products from two- and three-component reactions. B. measure the diversity and novelty of this library and how they differ from the world's in-stock molecules. C. Develop a community accessible database and chemoinformatics infrastructure that can store, similarity search, and rapidly retrieve molecules from this library. D. convert these molecules into biologically relevant 3D forms, including enumerating low- energy conformers, partial atomic charges and other parameters, van der Waals parameters and solvation energies for all library molecules, enabling their use for docking screens. Aim 2. Dock and experimentally test the library against two targets. A. Screen the library against the dopamine D4 and kappa-opioid receptors, seeking novel ligands. 250 to 500 library molecules will be tested per screen, itself a 10-fold increase. A key question will be do we find novel, potent ligands, or are we overwhelmed by false positives? B. As the library grows, do we continue to find ever more novel, in some sense ever more perfect, high affinity ligands, or does discovery saturate? C. How does hit rate vary with docking score? As we will be testing hundreds of molecules, we can afford to investigate not only those with the highest docking ranks, but also molecules with mediocre and poor ranks. This has not been previously explored, certainly not at scale. If successful, this project will increase the number of molecules available to the community by 1000-fold, and demonstrate their utility for ligand discovery. Extensive preliminary results support its feasibility.

项目摘要 /摘要 尽管对扩大化学空间的兴趣非常兴趣，但多样化的数十亿个分子库仍然无法访问。在 原理，停靠虚拟库可以访问一些缺失的化学空间。这个想法到现在为止 被两个关键问题所困扰：1。容易合成的分子的预测是具有挑战性的，没有 诉诸崩溃多样性的策略； 2。众所周知，对接是不准确的。最近的两个进步 使虚拟图书馆对接屏幕似乎不那么幻想了。首先，我们在Enamine的合作者，一个广泛使用的 优质化学物质供应商已根据> 100个反应定义了7亿分子的需求库 他们的控制权很好；其中>已成功合成了65万。第二，而 停靠保留了严重的错误，它取得了务实的进步，并找到了> 100的真正新颖的配体 目标。具体目的是： AIM 1。一个具有30亿种铅样分子的可靠，可搜索和可扩展数据库。我们将A。 从两组和三组分反应中列举了30亿个审查产品。 B.衡量多样性和 这个图书馆的新颖性以及它们与世界内库存分子的不同。 C.开发一个可访问的社区 可以存储，相似性搜索和快速检索分子的数据库和化学信息授权基础架构 来自这个库。 D.将这些分子转换为具有生物学相关的3D形式，包括列举低 - 能量构象体，部分原子电荷和其他参数，范德华参数和溶剂化 所有库分子的能量，使它们用于对接屏幕。 AIM 2。对接并实验测试库针对两个目标。答：筛选图书馆与多巴胺 D4和Kappa-Apoid受体寻求新型配体。每个屏幕将测试250至500个库分子， 本身增加了10倍。一个关键的问题是我们找到新颖，有效的配体，或者我们被误报所淹没 积极的？ B.随着图书馆的增长，我们是否继续发现越来越新颖，从某种意义上说， 高亲和力配体，还是发现饱和？ C. HIT率与对接得分有何不同？我们将 测试数百个分子，我们不仅可以调查那些停靠等级的分子，而且还可以调查 也具有平庸和较差的分子。以前尚未探索这一点，当然不是大规模的。 如果成功，该项目将使社区可用的分子数量增加1000倍，并且 展示他们的配体发现实用性。广泛的初步结果支持其可行性。