Toward Practical, Rigorous Binding Affinity Calculations

走向实用、严格的结合亲和力计算

基本信息

批准号：
7752865
负责人：
DANIEL M ZUCKERMAN
金额：
$ 23.32万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7752865
关键词：
Accounting Address Affect Affinity Agonist Algorithms Area Back Benchmarking Binding Binding Sites Biological Biological Models Biophysics Carbon Cardiovascular Agents Chemicals Clinical Collaborations Complex Computer software Computers Cost Savings Data Distant Docking Drug Design Engineering Ensure Equilibrium Estrogen Receptors Estrogens Family Free Energy Freezing Goals Individual Lead Libraries Ligand Binding Domain Ligands Location Measures Methods Modeling Molecular Molecular Conformation Molecular Models Motivation Nature Nuclear Hormone Receptors Octanols Osteoporosis Pathway interactions Pharmaceutical Preparations Play Positioning Attribute Preparation Principal Investigator Procedures Production Protein Binding Protein Isoforms Proteins Relative (related person)Research Research Personnel Roentgen Rays Role Sampling Scheme Series Site Solubility Solutions Speed Statistical Mechanics Structure System Techniques Testing Time Universities Update Vertebral column Washington Work base chemical group clinically relevant computer studies computing resources cost design drug candidate experience flexibility improved innovation interest malignant breast neoplasm molecular dynamics molecular mechanics molecular modeling novel programs receptor receptor binding scaffold simulation small molecule virtual willingness

项目摘要

DESCRIPTION (provided by applicant): Ideal, rigorous binding affinity computations, based on statistical mechanics, would fully account for ligand and receptor (protein) flexibility, as well as non-additive effects, which cannot properly be included in faster, more approximate estimates. Such ideal calculations, however, push the limits of present-day computational resources, and therefore have had limited practical impact. Furthermore, rigorous affinity estimates also suffer from errors in the assumed forcefields, which may lead to inaccuracies even when well-designed, well- converged calculations are performed. This proposal aims to take important steps toward overcoming these obstacles, and thus to make rigorous affinity estimation a practical, reliable part of the modeler's toolkit. The issue of computational cost will be addressed with innovative, efficient methods; accuracy will be addressed by the use of both standard and polarizable forcefields; and, lastly, molecular flexibility will be addressed using novel end-point (non- "alchemical") methods and a new conformational sampling scheme. The estrogen receptor is a system which truly embodies all the challenges of affinity calculations, possessing a great diversity of ligands, some of which induce a large receptor conformational change. Beyond its far- reaching clinical importance, the estrogen-receptor is a key model system for understanding binding phenomena in nuclear hormone receptors. Our strategies for improving rigorous affinity calculations will be pursued in the estrogen receptor system, in a series of tasks of increasing complexity. First, estrogen receptor ligands will be studied in solution, then in simplified models of the receptor binding site, and finally the full system will be investigated. With a local experimental collaborator, we will attempt to engineer compounds of potential clinical importance. Successful computational approaches will be implemented in widely available software packages.

描述（由申请人提供）：基于统计力学的理想，严格的结合亲和力计算将充分说明配体和受体（蛋白质）柔韧性以及非添加效应，这些效应无法正确包含在更快的估计速度中。但是，这种理想的计算推动了当今的计算资源的限制，因此实际影响有限。此外，严格的亲和力估计还遭受假定力场的错误，即使执行精心设计，融合良好的计算，也可能导致不准确。该建议旨在采取重要步骤来克服这些障碍，从而使严格的亲和力估算成为建模者工具包的实用，可靠的一部分。计算成本的问题将通过创新，有效的方法来解决；使用标准和两极分化的力场将解决精度；最后，将使用新颖的终点（非“炼金术”）方法和一种新的构象采样方案来解决分子柔韧性。雌激素受体是一个真正体现了亲和力计算的所有挑战，具有大量配体的系统，其中一些诱导大型受体构象变化。雌激素受体是一种关键模型系统，是理解核激素受体中结合现象的关键模型系统。我们改善严格亲和力计算的策略将在雌激素受体系统中采用一系列复杂性的任务。首先，将在溶液中研究雌激素受体配体，然后在受体结合位点的简化模型中研究，最后将研究完整的系统。通过本地实验合作者，我们将尝试设计具有潜在临床重要性的化合物。成功的计算方法将在广泛可用的软件包中实现。