Predictive P450 Toxicology: Metabolism and Polymorphisms

预测 P450 毒理学：代谢和多态性

• 批准号: 6852665
• 负责人: DANNI L HARRIS
• 金额: $ 23.53万
• 依托单位: MOLTECH CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-11 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6852665
• 关键词: chemical structure; computer program /software; computer system design /evaluation; cytochrome P450; drug metabolism; method development; pharmacogenetics; protein isoforms; single nucleotide polymorphism; thermodynamics; toxicology; toxicology information system

DESCRIPTION (provided by applicant): Toxic and carcinogenic side effects of drug administration are often due to their cytochrome P450 (CYP450) metabolism. It has been estimated that 1-in 15 hospital admissions is due to adverse drug effects. In addition, prescribed drugs account for 106,000 deaths and 2.2 million adverse reactions. Both interindividual and population subgroup variations in metabolism of drugs and xenobiotics have profound clinical consequences. The ability to predict metabolism at the earliest stage of drug discovery would accelerate the pace by which efficacious agents lacking toxicity are developed. This approach also takes advantage of the growing pharmacogenetics knowledge pertaining to both genotypic and phenotypic effects on drug metabolism. Rapid progress in our understanding of the underlying principles of CYP450 metabolism has resulted from the convergence of structural and molecular biology with theoretical methods, capable of predicting the geometric and thermodynamic determinants of competitive metabolism. This has enabled us to predict the principal products of CYP450 metabolism of drugs by a combination of ligand-P450 configurational sampling, based on rapid flexible docking, and electronic determinants of metabolism by the active heme species of P450s. Critical appraisals of this approach indicate a robust ability to predict major metabolites of test drugs, including toxic products, such as N-acetyl-p-benzoquinoneimine derived from CYP2E1 acetaminophen metabolism. This initial appraisal will be extended to test predictions of an assembled large 3D structural drug database with associated metabolic and kinetic data. The overall goal of this Phase I SBIR is twofold: 1) to critically assess a method capable of making metabolism predictions of drugs, by the major mammalian CYP450 isoforms, on the timescale of minutes per lead compound using a desktop computer, and 2) the extension of this method to predict the effects of single nucleotide polymorphisms (SNPs) on metabolism. This dual approach will establish an in silico predictive toxicology product developed with corporate partnership in a phase II application, that will be invaluable, even at the earliest stages of molecular conception, to the drug discovery process.

描述（由申请人提供）： 药物给药的毒性和致癌性副作用往往是由于其细胞色素P450（CYP 450）代谢。据估计，每15例住院病例中就有1例是由于药物不良反应。此外，处方药导致10.6万人死亡，220万起不良反应。药物和异生物质代谢的个体间和群体亚组差异具有深远的临床后果。在药物发现的最早阶段预测代谢的能力将加快开发无毒性的有效药物的步伐。这种方法还利用了不断增长的药物遗传学知识，涉及药物代谢的基因型和表型效应。我们对CYP 450代谢基本原理的理解取得了快速进展，这是由于结构和分子生物学与理论方法的融合，能够预测竞争性代谢的几何和热力学决定因素。这使我们能够预测的主要产品的CYP 450代谢药物的配体-P450构型采样的组合，基于快速灵活的对接，和电子决定因素的活性血红素物种的P450的代谢。对该方法的关键评价表明，该方法具有预测受试药物主要代谢物的稳健能力，包括毒性产物，如CYP 2 E1对乙酰氨基酚代谢产生的N-乙酰基-对-苯醌亚胺。这一初步评估将扩展到测试预测的组装大型三维结构药物数据库与相关的代谢和动力学数据。本I期SBIR的总体目标有两个方面：1）使用台式计算机，通过主要哺乳动物CYP 450亚型，在每种先导化合物的分钟时间尺度上，对能够进行药物代谢预测的方法进行严格评估; 2）将该方法扩展至预测单核苷酸多态性（SNP）对代谢的影响。这种双重方法将建立一个在第二阶段应用中与公司合作开发的计算机预测毒理学产品，即使在分子概念的最早阶段，对药物发现过程也是非常宝贵的。