STRUCTURE BASED DESIGN: INHIBITOR OF HIV RT

Kuntz小组的活动主要涉及基于结构的 配体设计方法 我们感兴趣的是提取结构 信息与先进的算法;计算机图形例程， 显示结构;精化过程;交互能 最先进的势函数最小化;药物设计 工具，如DOCK和COMBIDOCK。 我们已经开始了一项计划， 具有计算搜索的有机合成（DIVERSIFY）。 DIVERSIFY，使用有机转换生成一个大家庭， 从特定的起点生产产品。 的试剂和/或 然后可以使用我们的DOCK技术筛选得到的化合物。 DOCK有机化学数据库检索软件包 推定配体的化合物一直是UCSF药物的中心方面， 设计努力。 这套程序有着广泛的应用 酶系统，核酸，以及一般来说，涉及 分子识别。该程序的当前版本使用AMBER 分子间势能函数，以评估拟定的结合 几何学 DOCK是为了提出新的先导化合物而开发的。 它 已经在各种各样的系统中成功地实现了这一目标， 包括最近未发表的工作，确定了新的抑制剂， HIV逆转录酶。 此外，还在以下方面取得了进展： 软件前端 抑制剂的组合文库设计 组织蛋白酶D与加州大学伯克利分校的Ellman实验室合作 已经发布，图形用户界面的第一步已经 制备了

The Kuntz group activities primariliy involve structure-based ligand design methods. We are interested in extracting structural information with advanced algorithms; computer graphics routines to display structures; refinement procedures; interactive energy minimization with state-of-the-art potential functions; drug design tools such as DOCK and COMBIDOCK. We have begun a program to couple organic synthesis (DIVERSIFY) with computational searching. DIVERSIFY, uses organic transformations to generate a large family of products from specified starting points. The reagents and/or resulting compounds can then be screening using our DOCK technology. The DOCK software package for searching data bases of organic compounds for putative ligands has been a central aspect of UCSF drug design efforts. This suite of programs has wide-ranging applications to enzyme systems, nucleic acids, and, in general, problems involving molecular recognition.The curren version of the program uses the AMBER intermolecular potential functions to evaluate proposed binding geometries. DOCK was developed to propose novel lead compounds. It has been successful in this goal in a wide variety of systems, including recent, unpublished work identifying novel inhibitors of the HIV reverse transcriptase. Progress has also been made on the software front. Combinatorial library design for inhibitors of cathepsin D in collaboration with the Ellman laboratory at UC Berkeley has been published and a first step at a graphical user interface has been prepared.