Development of computer drug design softwares for purpose of lead generation

蛋白质结晶学的成功结果为我们提供了生物大分子分子识别或药物与受体相互作用的具体而精细的图像。分子相互作用、稳定性、化学反应活性以及物理性质的计算机模拟对于设计新的活性结构是有用的。但是，这些技术对于生成具有新骨架结构的活性分子并不是很有效。本研究的目的是开发新的计算机药物设计方法和软件，以产生铅。我们在药物受体理论的基础上开发了两个程序系统。在受体(或目标大分子)的三维结构已知的情况下：模拟药物与受体的连接。在受体的药物结合部位内的每个三维网格点上计算的各种数据，反映了林丁部位的局部物理化学特征，用于实时估计药物与受体之间的相互作用能。该方法便于评价生物反应的构效关系和机理，构建与结合部位匹配良好的新结构。在受体结构未知的情况下，通过估计每个三维网格点的物理化学性质来叠加药物分子，并在叠加结构的基础上构建受体模型。这种方法能够解释活性相似但化学结构完全不同的分子之间的结构和活性之间的关系。

Successful results of protein crystallography gave us concrete and minute image of molecular recognition by biological macromolecules, or of drug-receptor interactions. Computer simulations of molecular interactions, stabilities, chemical reactivities as well as physical properties are useful for designing new active structures. But, these techiques are not efficient for generating active molecules with new skeletal structures.The aim of this research is to develop new methods and softwares of the computer drug design for the purpose of lead generation. We have developed two program systems on the basis of drug-receptor theory. In the case of three-dimensional structures of receptors (or target macromolecules) is known: simulate the linding of drugs to the receptor. Various data calculated at each three-dimensional grid point inside the drug binding site of receptor whick exhibit the local physical and chemical character of the linding site, are used for estimating the interaction energy between drug and receptor in realtime. This method facilitates the evaluation of the structure-activity relationships and mechanisms of biological reactions, and construct ion of new structures which can well fit to the binding site.In the case of the receptor structure is unknown: superpose the drug molecules by estimating physical and chemical characters at each three-dimensional grid point, and construct a receptor model on the basis of superposed structures. This method enables to explain the relationships between structures and activities among molecules with similar activities but quite different chemical structrues.