New Hydropathy-Based computer Tools for Drug Discovery

用于药物发现的新型基于水疗法的计算机工具

• 批准号: 7039020
• 负责人: GLEN EUGENE KELLOGG
• 金额: $ 20.82万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039020
• 关键词: X ray crystallography; binding sites; chemical structure; computational biology; computer program /software; computer simulation; computer system design /evaluation; drug design /synthesis /production; drug discovery /isolation; electric field; hydropathy; intermolecular interaction; ligands; macromolecule; nuclear magnetic resonance spectroscopy; physical model; structural biology; three dimensional imaging /topography

DESCRIPTION (provided by applicant): The overall aim of this project is to develop a novel integrated suite of software applications for predicting, refining and manipulating biomacromolecular structure, particularly with respect to computational virtual screening of drug candidates. Virtual screening of a panel of ligands against a biomacromolecule target requires a highly accurate model for the ligand binding site, as well as rapid and effective estimation of binding affinity. In many important drug discovery projects both of these requirements cannot be met. The two main goals of the proposed research are thus to: 1) improve the accuracy and relability of free energy scoring of putative protein-ligand complexes, and 2) enhance the quality of low-resolution structural models from x-ray, nmr or comparative modeling to make them useful as targets for virtual screening. The core technology for this research plan is based on the HINT (Hydropathic INTeractions) program/paradigm that exports (with reasonable speed and accuracy) both a unique empirical free energy forcefield and threedimensional graphics objects that encode significant structural information. A number of specific software tools will be created by this effort: a) an integrated docking system using HINT forcefield scoring; b) an automated computational titration program that evaluates the ionization state of residues and ligand functional groups to optimize ligand binding; c) a range of methods to predict and/or optimize water molecule locations in environments where water-mediated hydrogen bonding could impact ligand binding; d) a new de novo ligand design protocol based on three-dimensional hydropathy maps; and e) integrated crystallographic and NMR refinement program(s) using the hydropathic forcefield as a target function. This latter tool may be extended as an adjunct to homology modeling approaches to creating target structures, and may prove useful for defining models of inaccessible proteins. Specific collaborative arrangements are in place to apply these tools to a range of current drug discovery problems.

描述（由申请人提供）：该项目的总体目标是开发一套新颖的集成软件应用程序套件，用于预测、精炼和操纵生物大分子结构，特别是在候选药物的计算虚拟筛选方面。针对生物大分子靶标的一组配体的虚拟筛选需要高度准确的配体结合位点模型，以及快速有效的结合亲和力估计。在许多重要的药物发现项目中，这两个要求都无法满足。因此，本研究的两个主要目标是：1）提高假定的蛋白质-配体复合物自由能评分的准确性和可靠性，2）提高来自 X 射线、核磁共振或比较模型的低分辨率结构模型的质量，使其可用作虚拟筛选的目标。该研究计划的核心技术基于 HINT（Hydropathic INTERactions）程序/范式，该程序/范式（以合理的速度和精度）输出独特的经验自由能力场和编码重要结构信息的三维图形对象。这项工作将创建许多特定的软件工具： a) 使用 HINT 力场评分的集成对接系统； b) 自动计算滴定程序，评估残基和配体官能团的电离状态以优化配体结合； c) 预测和/或优化水分子在水介导的氢键可能影响配体结合的环境中的位置的一系列方法； d) 基于三维水病图的新配体设计方案； e) 使用亲水力场作为目标函数的集成晶体学和核磁共振精化程序。后一种工具可以扩展为同源建模方法的辅助手段来创建目标结构，并且可能对于定义不可接近的蛋白质模型有用。已经制定了具体的合作安排，将这些工具应用于当前的一系列药物发现问题。