STRUCTURAL BIOLOGY AS APPLIED TO THE PROBLEM OF TARGETED DRUG DESIGN

如今，新药的开发变得越来越复杂。它 一种新的化合物有效是不够的，它必须具有显著的 与现有化合物相比的优势--活性更强，副作用更少 效果更好，纯度更高。此外，一些最严重的人类 疾病，如艾滋病，对药物来说是一个很难移动的目标， 传统的随机筛选化合物的方法 活动就是不能赢得战斗。我们发明新事物的能力 化合物，以满足非常具体的目标是重要的，以挽救生命。 虽然在阐明三个方面取得了重大进展- 关键酶的三维结构，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 化学家仍在设计新的化合物， 手动地通过临时猜测，以及通过对原始数据的微小扰动， 铅化合物 该项目的主要目的是开发一种新的系统，发明， 发明化学结构以符合特定标准。相比 今天的计算机辅助设计系统帮助化学家发明， 发明的焦点是计算机的发明。我们的假设是， 如果编程得当，计算机可以成为更好的发明家 比化学家。这样一个系统的好处是，它可以改善 提高可销售化合物的产量，降低开发新化合物的成本， 毒品适当的基于计算机的发明系统将不受 化学家在多年的教育中形成的偏见， 训练今天的化学设计问题在很大程度上源于 原子的三维空间排列，一个区域， 化学家很难在头脑中想象新的排列。 本发明将应用于HIV蛋白酶抑制剂的设计 和胸苷酸合成酶（TS）。 这项研究的第二个主要目标是开发计算机算法 通过不断增长的蛋白质底物数据库进行类比推理， 晶体结构，以帮助预测潜在的网站和强度 结合一种拟议的酶抑制剂。我们假设 类比推理方法，我们以前开发的AIMB可以 可用于提取蛋白质底物中固有的知识 数据库，即使复杂性如此之大， 排除人工分析。提取的知识将是有帮助的 在设计新的先导化合物中， HIV蛋白酶来抑制病毒复制。此外，我们预计 本研究旨在提供有关构象的一般信息， 由底物结合引起的蛋白质变化，以及关于底物 由于与蛋白质结合而引起的构象变化。

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.