STRUCTURAL BIOLOGY AS APPLIED TO THE PROBLEM OF TARGETED DRUG DESIGN

今天的新药开发已经变得越来越复杂。它 光是一种新化合物是有效的还不够，它必须有显著的 与现有化合物相比的优势--活性更高，侧基更少 效果，以及更高的纯度。此外，一些最严肃的人类 艾滋病等疾病是药物难以移动的目标， 传统的对所需化合物的随机筛选 活动根本不是赢得这场战斗。我们发明新事物的能力 达到非常具体的目标的化合物对拯救生命很重要。 尽管在阐明这三个方面取得了重大进展- 关键酶的空间结构，在计算机图形显示和 蛋白质和核酸的分析，以及相关的化学 具有活性的结构，化学家们仍在设计新的化合物 通过临时猜测和对原始数据的微小扰动来手动进行 铅化合物。 这个项目的一个主要目标是开发一种新的系统，发明，用于 发明符合特定标准的化学结构。与之形成鲜明对比的是 今天的计算机辅助设计系统帮助化学家发明， 发明的重点是计算机的发明。我们的假设是 只要编程得当，计算机就能成为更好的发明家 而不是药剂师。这样一个系统的好处是它可以改进 提高适销对路化合物的成品率，降低新产品开发成本 毒品。适当的基于计算机的发明系统将不受 一位化学家在多年的教育和培训中形成的偏见 训练。今天的化学设计问题严重植根于 原子的三维空间排列，其中的一个区域 化学家在心理上很难想象出新的安排。 本发明将应用于HIV蛋白酶抑制剂的设计 和胸苷合成酶(TS)。 这项研究的第二个主要目标是开发计算机算法 从不断增长的蛋白质底物数据库中进行类比推理 有助于预测潜在位置和强度的晶体结构 结合一种建议的酶抑制剂。我们假设 我们之前在AIMB中开发的类比推理方法可以是 对提取蛋白质底物中固有的知识很有用 数据库，尽管它的复杂性如此之大，以至于虚拟 排除人工人工分析。所提取的知识将是有帮助的 在设计将选择性结合的新先导化合物方面的发明 抑制病毒复制的HIV蛋白酶。此外，我们预计 这项研究旨在提供有关构象的一般信息 底物结合引起的蛋白质变化，以及底物的左右 作为与蛋白质结合的结果的构象变化。

The development of new drugs today has become increasingly complex. It is not enough that a new compound be effective, it must have significant advantages over existing compounds--greater activity, fewer side effects, and greater purity. Further, some of the most serious human diseases, such as AIDS present such a difficult moving target for drugs, that the traditional random screening of compounds for the desired activity is simply not winning the battle. Our ability to invent new compounds to meet very specific objectives is important to saving lives. Although major advances have occurred in elucidating the three- dimensional structure of key enzymes, in computer graphic display and analysis of proteins and nucleic acids, and in correlating chemical structure with activity, chemists are still designing new compounds manually by as hoc guessing, and by minor perturbations of an original lead compound. A major aim of this project is to develop a new system, INVENTION, for inventing chemical structures to fit specific criteria. In contrast to computer-assisted design systems of today which help the chemist invent, the focus of INVENTION is invention by the computer. Our hypothesis, is that when properly programmed, the computer can be a better inventor than the chemist. The benefit of such a system is that it could improve the yield of marketable compounds and reduce the cost of developing new drugs. An appropriate computer-based invention system would be free from the bias that a chemist develops over the years of education and training. Today's chemical design problems are heavily rooted in the three-dimensional spatial arrangement of atoms, an area in which chemists have great difficulty mentally visualizing new arrangements. INVENTION will be applied to the design of inhibitors of HIV protease and the enzyme thymidylate synthase (TS). A second major aim in this research is to develop computer algorithms for reasoning by analogy from the growing database of protein-substrate crystal structures to help predict the potential site and strength of binding of a proposed enzyme inhibitor. We hypothesize that the analogical reasoning methodology we developed previously in AIMB can be useful in extracting knowledge that is inherent in the protein-substrate database, even though the complexity is so great as to virtually preclude manual human analysis. The knowledge extracted will be helpful to INVENTION in designing new lead compounds that will selectively bind to the HIV protease to inhibit virus replication. Additionally we expect this study to provide general information about the conformational changes in the protein caused by substrate binding, and about substrate conformational changes as a result of binding to the protein.