Development of computer system for generating drug structures based on drug-receptor interaction

虽然先导化合物对药物开发的成功非常重要，但如果没有机会，很难人工发现或产生先导化合物。然后，我们开发了两种新的方法和程序来生成可能的配体结构，它们提供了有利于与靶受体结构或受体模型结合的形状和性质。在众多这样的结构中，我们可以合成少量的结构，这些结构是从化学和合成的角度选择和修饰的。其中之一是一个名为Legend的程序，它根据受体配体结合区的力场和随机数构建一个接一个产生原子的分子。该程序可以产生不仅与受体腔很好匹配的结构，而且还能尽可能多地与受体形成氢键。我们将这个程序应用于二氢叶酸还原酶(E.Coli)，它的三维结构已经被晶体学阐明。结果表明，生成的结构比较稳定，分子内和分子间的结构都很稳定，并且种类繁多。另一种方法是基于已知配体(药物或天然生物活性化合物)的活性结构。该方法自动构建可能的骨架结构，该骨架结构保持假定为生物活性所需的官能团的位置和取向。该程序适用于一种镇痛剂，吗啡，保存苯基和氮气。所得到的结构包括几个新的骨架结构以及几个已知的止痛药结构。

Although lead compound is very important for succeeding in drug development, it is so difficult to discoveror generate artificially without relying on chance. Then, we have developed two new methods and programs for generating possible ligand structures, which provide shapes and properties favorable for binding to the target receptor structures or receptor models. Among many such structures, we can synthsize a small number of structures which were selected and modified from the chemical and synthetic view point. One of them is a program, LEGEND, which construct molecules generating atoms one by one based on a force field and random numbers in the ligand binding region of the receptor. The program can generate structures which not only well fit to the receptor cavity but also form hydrogen bonds tothe receptor as many as possible. We have applied this program to an enzyme, dihydrofolate reductase(E. coli), whose 3Dstructure has been elucidated crystallographically. It was shown that generated structures were fairly stable intra- and intermolecularly and full of variety. A few of them are now under chemical syntheses, after iterative modification of the structure and computer simulation of the stability.Another method is that based on the active structures of known ligand(drugs or natural bio-acitve compounds). The method construct automatically possible skeletal structures which maintain positions and orientations of functional groups presumed to be required for the biological activity. The program was applied to an analgesics, morphine, preserving the phenyl and nitrogen lonepair. The resulted structures included several new skeletal structures together with several known analgesics structures.