Design and Experimental Testing of New Docking Methods

新对接方法的设计和实验测试

• 批准号: 7217284
• 负责人: Brian K Shoichet
• 金额: $ 26.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217284
• 关键词: Algorithms; Binding; Binding Sites; Biological Models; Charge; Communities; Crystallography; Cytochromes; Databases; Docking; Drug Binding Site; Experimental Designs; Experimental Models; Explosion; Freedom; Growth; Homology Modeling; Lactamase; Learning; Ligands; Methods; Modeling; Molecular; Muramidase; Peroxidase; Peroxidases; Phase; Pliability; Proteins; Role; Sampling; Score; Screening procedure; Side; Site; Solvents; Structure; System; Techniques; Testing; Ursidae Family; base; cost; improved; receptor; success

DESCRIPTION (provided by applicant): Structure-based screening using molecular docking is now widely used for ligand discovery. The technique makes many approximations and, although, it has had noteworthy successes, it is neither fully reliable nor do we understand why it fails when it does. Here, we develop model experimental systems where problems in docking may be isolated and understood. These systems are used to test new docking algorithms. The specific aims are: 1. To develop model experimental systems to test docking algorithms. We introduce seven model binding sites of increasing complexity. A. Five buried cavities in T4 lysozyme and cytochrome C peroxiadase: one purely hydrophobic, three bearing a single polar, cationic, and anionic residue, respectively, and a fifth that is anionic with several polar groups. These isolate polar, apolar, and ionic terms in docking scoring functions. B. A hydrophobic cavity in TEM-1, open to solvent at one end, that explores the influence of the protein-solvent interface in docking. C. AmpC B-lactamase, which has all the complexities of a drug-binding site, but is a system over which we have complete control. New docking methods will be tested experimentally against these model systems. Predicted geometries will be tested by crystallography and binding energies determined. In these systems, we expect to learn as much from "decoy" molecules that do not bind, as from those that do. These provide strong decoy sets for docking. Both the model systems and the decoys should be useful to the community. 2. To develop new docking algorithms. The docking problem is one of sampling available states, which grow exponentially with degrees of freedom, and evaluating their energies, difficult in condensed phases. To improve the energetic component in docking, we consider algorithms to A. calculate context-dependent ligand desolvation and B. receptor desolvation in docking. These key terms are often overlooked, owing to their high computational cost; the new methods should overcome this cost, albeit with important approximations. We also consider sampling C. receptor flexibility with an algorithm that scales only linearly with degrees of freedom, overcoming an otherwise exponential growth. This is extended to D. evaluate docking to homology models. All methods are tested experimentally against our model binding sites. Finally, we E. use the extensive sets of decoys developed in aim 1 to evaluate and improve docking algorithms.

描述（由申请人提供）：使用分子对接的基于结构的筛选现在广泛用于配体发现。该技术进行了许多近似，虽然它取得了显著的成功，但它既不完全可靠，我们也不理解为什么它会失败。在这里，我们开发的模型实验系统，在对接的问题可能会被隔离和理解。这些系统用于测试新的对接算法。具体目标是：1.开发模型实验系统，测试对接算法。我们介绍七个模型结合位点的复杂性不断增加。A. T4溶菌酶和细胞色素C过氧化物酶中有五个埋藏的空腔：一个是纯疏水性的，三个分别带有一个极性、阳离子和阴离子残基，第五个是阴离子，带有几个极性基团。这些隔离极性，非极性，和离子的对接评分功能。B。TEM-1中的疏水空腔，一端对溶剂开放，用于探索蛋白质-溶剂界面对对接的影响。C. AmpC B-内酰胺酶，它具有药物结合位点的所有复杂性，但我们可以完全控制它。新的对接方法将在这些模型系统上进行实验测试。预测的几何形状将通过晶体学和结合能测定进行测试。在这些系统中，我们期望从不结合的“诱饵”分子和那些结合的分子中学到同样多的东西。这为对接提供了强诱饵。模型系统和诱饵都应该对社区有用。2.开发新的对接算法。对接问题是一个采样可用的状态，这与自由度呈指数增长，并评估他们的能量，在凝聚相困难。为了改善对接中的能量分量，我们考虑A.计算上下文相关的配体去溶剂化和B。对接中的受体去溶剂化。这些关键的条款往往被忽视，由于他们的高计算成本;新的方法应该克服这种成本，虽然重要的近似。我们还考虑采样C。受体的灵活性与算法，规模只有线性的自由度，克服了否则指数增长。这是推广到D。评估与同源模型的对接。所有的方法进行了实验测试对我们的模型结合位点。最后，我们E。使用在目标1中开发的大量诱饵来评估和改进对接算法。