Theoretical Studies of Metalloprotein Chromophores

金属蛋白发色团的理论研究

基本信息

批准号：
7618423
负责人：
RICHARD A FRIESNER
金额：
$ 27.16万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-07-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7618423
关键词：
Academia Active Sites Address Affinity Algorithms Area Biochemical Reaction Biological Biological Models Biological Process Biotechnology Carrier Proteins Chemistry Collaborations Computer Simulation Computer software Computing Methodologies Cytochrome P450 Development Docking Drug Design Effectiveness Electrons Enzymes Event Exhibits Free Energy Freedom Goals Grant Health Hemoglobin Human Hydroxylation Industry Laboratories Lead Ligands Measurement Metabolic Metabolic Pathway Metabolism Metalloproteins Methane Methane hydroxylase Methodology Methods Modeling Molecular Mono-S Myoglobin Oxygenases Panthera onca Pharmacologic Substance Physical Chemistry Play Potential Energy Progress Reports Property Protein Isoforms Proteins Quantum Mechanics Reaction Relative (related person)Research Resolution Role Sampling Screening procedure Staging Structural Models Surface System Technology Theoretical Studies Theoretical model Time Transition Elements Triose-Phosphate Isomerase Work base biological systems chemical reaction chromophore conformational conversion density design drug metabolism electronic structure energy density graphical user interface insight interest ionization knowledge base metalloenzyme method development molecular mechanics novel novel strategies pre-clinical programs protein structure quantum chemistry research study theories tool user friendly software

项目摘要

DESCRIPTION (provided by applicant): The long term goal of this project is the development of computational methods that will enable accurate modeling of protein active site chemistry at an atomic level of detail, with a primary focus on metalloproteins. Such modeling will provide insight into biological functioning of metalloenzymes and transport proteins, and facilitate the design of pharmaceutically relevant compounds interacting with these systems. The computational methods that we are developing include new approaches to density functional theory, mixed quantum mechanics/molecular mechanics methods, sampling algorithms for treating protein conformational transitions, and algorithms to calculate overall free energy changes for chemical reactions of interest. Specific proteins to be studied in the proposed granting period include methane mono-oxygenase, cytochrome P450, and hemoglobin. Cytochrome P450, which plays a fundamental role in drug metabolism, will be a particular focus of the project. We will continue to work on understanding the fundamental mechanism of hydroxylation, but at the same time, building on promising preliminary results obtained over the past several years, will investigate the conformational plasticity of the active site which is a critical aspect of the ability of these enzymes to interact with a wide variety of compounds. A direct, health related goal of the project is to develop a suite of tools for creating a reliable structural and energetic model of pharmaceutically relevant compounds interacting with human P450 isoforms; such a model would be immediately useful the late stages of lead optimization to modify preclinical candidates which exhibit problems with P450 metabolism.

描述（由申请人提供）：该项目的长期目标是开发计算方法，该方法将能够在原子细节水平上对蛋白质活性位点化学进行精确建模，主要关注金属蛋白质。这种建模将提供对金属酶和转运蛋白的生物功能的深入了解，并促进与这些系统相互作用的药学相关化合物的设计。我们正在开发的计算方法包括密度泛函理论的新方法、混合量子力学/分子力学方法、用于处理蛋白质构象转变的采样算法以及计算感兴趣的化学反应的总体自由能变化的算法。在拟议的资助期内要研究的具体蛋白质包括甲烷单加氧酶、细胞色素 P450 和血红蛋白。细胞色素 P450 在药物代谢中发挥着基础作用，将成为该项目的特别关注点。我们将继续致力于了解羟基化的基本机制，但同时，在过去几年获得的有希望的初步结果的基础上，我们将研究活性位点的构象可塑性，这是这些能力的一个关键方面。酶与多种化合物相互作用。该项目的一个直接的、与健康相关的目标是开发一套工具，用于创建与人类 P450 同种型相互作用的药物相关化合物的可靠结构和能量模型；这种模型将在先导化合物优化的后期立即发挥作用，以修改存在 P450 代谢问题的临床前候选药物。