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至关重要，但不依赖偶然性，人工合成或合成先导化合物是非常困难的。然后，我们开发了两种新的方法和程序，用于产生可能的配体结构，其提供有利于结合到靶受体结构或受体模型的形状和性质。在许多这样的结构中，我们可以从化学和合成的角度来选择和修饰少量的结构。其中之一是一个程序，LEGEND，它构建分子，根据力场和受体配体结合区的随机数逐个产生原子。该程序不仅可以生成与受体空腔相匹配的结构，而且可以生成尽可能多的与受体形成氢键的结构。我们已经将该程序应用于酶，二氢叶酸还原酶（E。coli），其三维结构已被晶体学解析。结果表明，所生成的结构在分子内和分子间相当稳定，且具有丰富的多样性。其中一些化合物目前正在化学合成中，经过反复的结构修饰和计算机模拟稳定性，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，其保持假定为生物活性所需的官能团的位置和取向。该程序被应用于一种镇痛药，吗啡，保留了苯基和氮的孤对。所得到的结构包括几个新的骨架结构以及几个已知的镇痛剂结构。

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.