Fundamentals of Ligand-Protein Interactions

配体-蛋白质相互作用的基础知识

• 批准号: 7592979
• 负责人: MARC NICKLAUS
• 金额: $ 10.87万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592979
• 关键词: Active Sites; Binding; Binding Sites; Chemicals; Complex; Computer software; Data; Data Set; Databases; Drug Design; Drug effect disorder; Enzymes; Ligands; Light; Methodology; Molecular Conformation; Numbers; Pharmaceutical Preparations; Process; Protein Binding; Proteins; PubMed; Publications; Resources; Site; Source; Structure; Time; Vacuum; X-Ray Crystallography; numb protein; quantum; small molecule; theories

The conformational changes of both partners of a ligand-protein complex, the small-molecule ligand its the protein binding site (in many cases the catalytically active site of an enzyme) are a central aspect many drug actions, as well as a crucial challenge in computational approaches to drug design. In one of the earliest publications in the this field, we <A HREF="http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=8581425&ordinalpos=47&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum">showed</A> for a small set of ligands occurring both in the Protein Data Bank (PDB) and the Cambridge Structural Database (CSD) that flexible compounds are not usually bound to a protein in their global vacuum energy conformation, and oftentime not even in any local vacuum energy conformation. <BR> While this study used the largest set of data and best methodology available at that time, both the number of structures in either experimental database and the software and hardware resource available have since grown exponentially. <BR> We are thus revisiting this important topic with an analysis of orders of magnitudes more structures, and computations performed at a high level of computational quantum-chemical theory. <BR> Among other milestones achieved so far in this project, we have extracted all occurrences of small-molecule ligands in the PDB with their 3D coordinates, and with extensive annotation added, combined from several different sources. As of August 2007, this is a set of over 106,000 structures. This will allow us to conduct a detailed analysis not only of the conformational changes observed in protein-ligand crystal structures, but also of potential quality issues of these crystal structures themselves.

配体 - 蛋白质复合物的两个伴侣的构象变化，小分子配体的蛋白结合位点（在许多情况下，酶的催化活性位点）是许多核心方面的许多药物作用，也是计算方法的重要挑战。在该领域最早的出版物之一中，我们<a href =“ http://www.ncbi.nlm.nih.gov/sites/entrez?db = pubmed&cmd = showdetailview＆termtosearch = 8581425 ＆ordinalpos = 47＆itool = entrezsystem2.pentrez.pubmed.pubmed_resultspanel.pubmed_rvdocsum”>显示</a>对于蛋白质数据库（PDB）和剑桥结构数据库（CSD）中发生的一小部分配体，柔性化合物通常不与其全球真空能构象中的蛋白质结合，甚至在任何局部真空能量构象中都没有结合。 <br>这项研究使用了当时可用的最大数据和最佳方法，但自那以后，实验数据库中的结构数量以及可用的软件和硬件资源的数量呈指数增长。 <br>因此，我们正在通过分析大小的更多结构，并以高度计算量子化学理论进行的计算来重新审视这一重要主题。 <br>在该项目到目前为止取得的其他里程碑外，我们还提取了PDB中的所有小分子配体及其3D坐标的所有发生，并添加了广泛的注释，并从几种不同来源组合在一起。截至2007年8月，这是一组超过106,000个结构。这将使我们不仅可以对蛋白质晶体结构中观察到的构象变化进行详细的分析，还可以对这些晶体结构本身的潜在质量问题进行详细分析。