COMPUTATIONAL SCREENING FOR LEAD COMPOUNDS

近年来，高分辨率结构的可用性 酶-抑制剂复合物的发现， 分子间相互作用 利用这些结构信息， 基于计算机的方法有助于识别或设计配体， 与分子筛上的各个位点具有良好的空间和化学互补性， 酵素 这一过程被称为“基于结构的分子生物学”。 设计”。 这项工作的长期目标是开发一种方法， 通过计算筛选和评估配体作为潜在的铅 化合物. 我们正在寻求一种既快速又合理的方法 准确 由Kuntz小组开发的DOCK程序套件， 识别和表征受体或蛋白质上的位点， 抑制剂结合;定向分子数据库;并评估 这些分子的拟合度。 位置标识和 表征传统上由程序SPHGEN完成。 最近，我们开发了一种新的方法，称为SURFSPH， 确定蛋白质上假定的原子位置。 这个程序可以 也被用来帮助定位酶之间的差异， 不同的物种，并作为配体修饰的辅助。 MidasPlus拥有 在这里被用来可视化和显示这些球体（见1）。 此外，MidasPlus与midas委托一起使用--沿着， Viewdock，检查不同的构象和方向， DOCK输出的配体。 这是工作的延续 鉴定了酶的抑制剂， 黄嘌呤-次黄嘌呤-鸟嘌呤-磷酸核糖转移酶。

In recent years, the availability of high resolution structures of enzyme-inhibitor complexes have led to an increased understanding of molecular interactions. Using this structural information, computer-based approaches help identify or design ligands that posses good steric and chemical complementarity to various sites on the enzyme. This process is referred to as "structure-based molecular design". The long term objective of this work is to develop a method tocomputationally screen and evaluate ligands as potential lead compounds. We are seeking a method that is rapid and reasonably accurate. The DOCK suite of programs, developed by the Kuntz group, identifies and characterizes sites on a receptor or protein for inhibitor binding; orients a database of molecules; and evaluates these molecules for goodness of fit. Site identification and characterization has traditionally be done by the program SPHGEN. More recently, we have developed a new method, called SURFSPH, which identifies putative atom positions on the protein. This program can also been used to help locate differences between enzymes from different species and as an aid in ligand modification. MidasPlus has been used here to visualize and display these spheres (see 1). Additionally, MidasPlus is used--along with the midas delegate, Viewdock, to examine different conformations and orientations of ligands from the DOCK output. This is a continuation of the work which identified inhibitors of the enzyme, xanthine-hypoxanthine-guanine-phosphoribosyl transferase, xhg-ptrase.