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Novel Computational Methods for Modeling Cytochrome P450 Mediated Drug Metabolism

细胞色素 P450 介导的药物代谢建模的新计算方法

基本信息

批准号：
8706177
负责人：
Markus Alexander Lill
金额：
$ 19.99万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8706177
关键词：
Address Adverse reactions Affinity Applications Grants Binding CYP2C9 gene CYP3A4 gene Chemicals Collaborations Collection Computer Simulation Computing Methodologies Cytochrome P450 Data Databases Descriptor Development Docking Drug Interactions Drug Metabolic Detoxication Drug Metabolism Inhibition Electronics Entropy Enzyme Inhibition Enzyme Interaction Enzymes Feedback Human Hydrogen Individual Internet Ligand Binding Ligands Measures Mediating Metabolic Methodology Methods Modeling Multienzyme Complexes Performance Pharmaceutical Preparations Phase Play Property Proteins Protocols documentation Publications Quantitative Structure-Activity Relationship Research Research Infrastructure Research Personnel Roentgen Rays Role Secure Site Structure System Techniques Water Xenobiotic Metabolism Xenobiotics base computer infrastructure computer studies design drug candidate drug clearance drug development drug discovery drug metabolism flexibility functional group improved inhibitor/antagonist innovation insight interest models and simulation novel public health relevance quantum research study screening simulation tool virtual

项目摘要

DESCRIPTION (provided by applicant): The metabolism of drugs and other xenobiotics by cytochrome P450 enzymes (CYP) is an essential detoxification and drug clearance mechanism in humans. Despite the publication of several X-ray structures since 2000, reliable computational prediction of drug metabolism remains a huge challenge. In this grant application, we propose an integrative high-throughput approach that combines electronic properties of a ligand with structural properties of the protein. Our main aim is the development and application of innovative structure-based design techniques that address serious shortcomings of current approaches. In particular, we have extended our novel docking concept to incorporate all observed forms of protein flexibility relevant for ligand-CYP interactions, entropic contributions influencing the prediction of binding poses, and we will add on- the-fly solvation to ligand-CYP complexes. To improve the docking quality we will optimize the parameters of a scoring function tailor-made for each CYP enzyme studied. In combination with an initial focus on efficient calculation of hydrogen-abstraction energies we will predict regioselective metabolism of drugs or drug candidates binding to CYPs. Based on the resulting docking poses, multidimensional QSAR simulations will be performed for accurate quantification of binding affinity as a measure CYP-inhibition and better ranking of binding modes. The new computational methods will be applied to two CYP enzymes (CYP2C9, 3A4) important in drug metabolism. The generated computational models will be stored in a database and made publicly available. Other researchers will be invited to screen compounds against our CYP database via a secure Web protocol to predict drug metabolism and inhibition. The submission of data by other researchers will provide valuable feedback on the performance and applicability of the models.

描述（由申请人提供）：细胞色素 P450 酶（CYP）对药物和其他外源物质的代谢是人类重要的解毒和药物清除机制。尽管自 2000 年以来已经发表了多种 X 射线结构，但药物代谢的可靠计算预测仍然是一个巨大的挑战。在这项拨款申请中，我们提出了一种综合高通量方法，将配体的电子特性与蛋白质的结构特性相结合。我们的主要目标是开发和应用基于结构的创新设计技术，以解决当前方法的严重缺陷。特别是，我们扩展了我们的新颖对接概念，以纳入与配体-CYP相互作用相关的所有观察到的蛋白质灵活性形式、影响结合姿势预测的熵贡献，并且我们将在配体-CYP复合物中添加动态溶剂化。为了提高对接质量，我们将优化为所研究的每种 CYP 酶量身定制的评分函数的参数。结合最初对氢抽象能量的有效计算的关注，我们将预测药物或候选药物与 CYP 结合的区域选择性代谢。基于所得的对接姿势，将进行多维 QSAR 模拟，以准确量化结合亲和力，作为 CYP 抑制的衡量标准和更好的结合模式排名。新的计算方法将应用于药物代谢中重要的两种 CYP 酶（CYP2C9、3A4）。生成的计算模型将存储在数据库中并公开可用。其他研究人员将被邀请通过安全的网络协议根据我们的 CYP 数据库筛选化合物，以预测药物代谢和抑制。其他研究人员提交的数据将为模型的性能和适用性提供有价值的反馈。