Covalent Binding Methods for Early Drug Development

描述(由申请人提供)： 这项建议的总体目标是开发一种高通量方法，可用于评估早期药物开发中共价结合的潜力。这种新的方法将允许快速和廉价地确定毒物学特征。目前，鉴定共价中间体通常需要标记的化合物或标记蛋白的抗体。这些方法繁琐，不容易进行高通量筛选。最近，共价加合物已经用质谱学方法进行了表征。我们在这里提出的方法使用类似的工具，如质谱学，但加合物表征应该快得多，因为将对所有化合物分析相同(或少量)的肽片段。这项提案中概述的努力如果成功，可能会对目前办法下开发药物的方式产生重大影响。缩短将药物推向市场所需的时间，可以帮助制药公司以具有成本效益的方式满足老龄化和医疗保健密集型人口急剧增长的需求，从而产生重大的社会和经济影响。由于安全和毒性问题目前占据了新药开发所需时间和资金的最大比例，这项提案旨在显著提高新药开发的效率和该国目前的医疗保健水平。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop a high throughput method that can be used to assess the potential for covalent binding in early stage drug development. This novel method will allow for the determination of toxicological profiles quickly and cheaply. Currently, the identification of covalent intermediates typically requires a radiolabeled compound or an antibody to the labeled protein. These methods are tedious and are not easily amenable to high throughput screening. More recently, covalent adducts have been characterize by mass spectrometric methods. The method we propose herein employs similar tools, such as mass spectrometry, but adduct characterization should be much more rapid since the same (or a small number) of peptide fragments would be analyzed for all compounds. The efforts outlined in this proposal, if successful, could serve to significantly impact the way in which drugs are developed under the current approach. The reduction in the time required to bring drugs to market can have a significant social and economic impact by helping drug companies meet the steeply increasing demands of an aging, and more health-care intensive population in a cost effective way. With safety and toxicity issues currently usurping the largest portion of time and money requirements for new drug development, this proposal aims to significantly improve the efficiency of new drug development and the current level of healthcare in this country.