Tools for Prediction of Drug Metabolism and Metabolites

这是CADD小组与国防部（DoD）的几个小组联合项目的一部分，该项目名为“将小分子转化为研究性新药的计算平台”。国防部方面的项目负责人是S. Anders Wallqvist博士，三军生物技术高性能计算软件应用研究所（BHSAI），远程医疗和先进技术研究中心（TATRC），美国陆军医学研究和装备司令部（USAMRMC）， 2405 Whittier Drive, Suite 200, Frederick, MD 217602。其他参与小组在沃尔特·里德陆军研究所生物化学系（WRAIR）和美国陆军传染病医学研究所细胞生物学和生物化学系（USAMRIID）。整个项目的目标是整合临床前药物开发阶段的三个基本方面，即基于结构的药物设计，药理数据的分析和预测，以及化学结构的不良和脱靶效应预测。作为一个特定的初始目标，这个项目总体上，特别是CADD小组的Pugliese博士，将对特定病原体的几种酶应用基于结构的抑制剂设计方法。Pugliese博士将应用同源建模、对接、药效团搜索、ADME/Tox预测程序、代谢分析和其他在CADD工作中有用的计算工具等方法来识别病原体靶点的小分子，这些小分子作为候选分子，最终可能导致针对这种病原体和使用类似酶的其他病原体的药物。Pugliese博士工作的最重要方面将涉及新陈代谢和代谢物。这项工作于2010年初有效开始，Pugliese博士已经开始实施一种资源，用于成功预测药物样小分子的代谢和代谢物，作为我们计算机辅助药物设计能力的一部分。该项目的第一阶段即将完成，包括对预测计算机工具以及可用于测试这些工具和开发（更好的）预测模型的数据集进行实地调查。商业资源和免费资源都已编译或正在获取过程中。一项比较和基准研究正在进行中，并将适当发表。在这个项目的初始阶段，我们专注于（预测）代谢稳定性数据，如人肝微粒体或人肝细胞测定中的半衰期值。计划将研究范围扩大到预测代谢反应类型和代谢部位以及代谢产物；和细胞色素P450代谢谱，包括预测化合物是特定同工酶的抑制剂还是诱导剂。虽然这些资源的初始测试和应用将在国防部感兴趣的病原体的背景下进行，但预测小分子代谢稳定性、代谢谱和特定代谢物的一般能力将适用于所有类型的药物开发，因此在NCI高度感兴趣的分子靶点的抗癌治疗药物的开发中非常有用，以及在NCI的抗hiv药物设计项目中。

This is a part of a joint project of the CADD Group with several groups at the Department of Defense (DoD), with the title Computational platforms for transforming small molecules into investigational new drugs. The projects lead PI on the DoD side is Dr. S. Anders Wallqvist, Tri-Service Biotechnology High-Performance Computing Software Applications Institute for Force Health Protection (BHSAI), Telemedicine and Advanced Technology Research Center (TATRC), U.S. Army Medical Research and Materiel Command (USAMRMC), 2405 Whittier Drive, Suite 200, Frederick, MD 217602. Other participating groups are at the Department of Biochemistry, Walter Reed Army Institute of Research (WRAIR), and the Department of Cell Biology and Biochemistry, U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID). The aim of the overall project is to integrate three fundamental aspects of the preclinical drug development phase, i.e., structure-based drug design, analysis and prediction of pharmacological data, and the prediction of adverse and off-target effects from chemical structures. As a specific initial target, this project in general, and Dr. Pugliese in the CADD Group in specific, will apply structure-based inhibitor design approaches to several enzymes of a specific pathogen. Dr. Pugliese will apply approaches such as homology modeling, docking, pharmacophore searches, ADME/Tox prediction programs, metabolic profiling and other computational tools useful in CADD work to the pathogens target(s) to identify small molecules as candidates that could ultimately lead to drugs against this and other pathogens employing similar enzymes. The most important aspect of Dr. Pugliese's work will concern metabolism and metabolites. The work having effectively started in early 2010, Dr. Pugliese has begun to implement a resource for successful prediction of metabolism and metabolites of drug-like small molecules as part of our computer-aided drug design capabilities. The first phase of this project, consisting of canvassing the field for predictive computer tools as well as data sets that can be used to test these tools and develop (better) predictive models, is nearing completion. Both commercial and free resources have been compiled or are in the process of being acquired. A comparison and benchmark study with appropriate publication is in the works. In this initial phase of the project, we are focusing on (prediction of) metabolic stability data such as half-life values in Human Liver Microsome or Human Hepatocyte assays. It is planned to broaden the scope of properties studied to prediction of type of metabolization reaction and metabolization site as well as of metabolites; and cytochrome P450 metabolization profiles including prediction whether a compound is an inhibitor or an inducer of a specific isozyme. While the initial test and application of these resources will occur in the context of the pathogen of interest to DoD, the general capability of predicting metabolic stability, metabolization profile and specific metabolites of a small molecule will be applicable to all types of drug development, and therefore be very useful in the development of anti-cancer therapeutics aiming at molecular targets of high interest to NCI, as well as in, e.g., NCI's anti-HIV drug design projects.