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

基本信息

批准号：
7587410
负责人：
GLEN EUGENE KELLOGG
金额：
$ 20.49万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7587410
关键词：
Accounting Active Sites Affinity Arts Binding Binding Proteins Binding Sites Complex Computer software Computers Consensus Cryoelectron Microscopy Crystallography Data Databases Development Docking Drug Design Effectiveness Environment Free Energy Generations Goals Homology Modeling Hydrogen Bonding Hydrophobicity In Situ Lead Ligand Binding Ligands Location Maps Mediating Membrane Methodology Methods Modeling Molecular Molecular Models Positioning Attribute Principal Investigator Procedures Proteins Protocols documentation Research Resolution Screening procedure Series Set protein Software Tools Solvents Speed Structural Models Structure System Technology Testing Titrations Validation Virtual Tool Water base comparative computerized tools design drug candidate drug discovery functional group hydropathy improved interest ionization meetings molecular modeling novel programs research study small molecule structural biology success tool virtual water environment

项目摘要

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、核磁共振或比较的低分辨率结构模型的质量。建模以使它们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。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Computational analysis of structure-based interactions and ligand properties can predict efflux effects on antibiotics.

基于结构的相互作用和配体特性的计算分析可以预测抗生素的外排效应。

DOI：
10.1016/j.ejmech.2012.03.008
发表时间：
2012-06
期刊：
European journal of medicinal chemistry
影响因子：
6.7
作者：
Sarkar A;Anderson KC;Kellogg GE
通讯作者：
Kellogg GE

Tools for building a comprehensive modeling system for virtual screening under real biological conditions: The Computational Titration algorithm.

用于构建真实生物条件下虚拟筛选综合建模系统的工具：计算滴定算法。

DOI：
发表时间：
2006-05
期刊：
影响因子：
0
作者：
Kellogg, Glen E;Fornabaio, Micaela;Chen, Deliang L;Abraham, Donald J;Spyrakis, Francesca;Cozzini, Pietro;Mozzarelli, Andrea
通讯作者：
Mozzarelli, Andrea

Robust classification of "relevant" water molecules in putative protein binding sites.

推定蛋白质结合位点中“相关”水分子的稳健分类。

DOI：
10.1021/jm701023h
发表时间：
2008-01-31
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Alessio Amadasi;J. A. Surface;F. Spyrakis;P. Cozzini;A. Mozzarelli;G. Kellogg
通讯作者：
G. Kellogg

Bound water at protein-protein interfaces: partners, roles and hydrophobic bubbles as a conserved motif.

蛋白质-蛋白质界面处的结合水：伙伴、角色和作为保守基序的疏水气泡。

DOI：
发表时间：
2011
期刊：
影响因子：
3.7
作者：
Ahmed MH;Spyrakis F;Cozzini P;Tripathi PK;Mozzarelli A;Scarsdale JN;Safo MA;Kellogg GE
通讯作者：
Kellogg GE

Energy-based prediction of amino acid-nucleotide base recognition.

基于能量的氨基酸-核苷酸碱基识别预测。

DOI：
发表时间：
2008-09
期刊：
影响因子：
3
作者：
Marabotti, Anna;Spyrakis, Francesca;Facchiano, Angelo;Cozzini, Pietro;Alberti, Saverio;Kellogg, Glen E;Mozzarelli, Andrea
通讯作者：
Mozzarelli, Andrea