Development of new methods and softwares for drug design using computer graphics

计算机和三维计算机图形(3D-CG)是进行合理药物设计的有力工具。它们有助于我们理解三维结构和生物大分子对分子的识别，并为我们提供逻辑性和量化。分子相互作用、物理性质等计算机模拟可以为我们设计新的活性结构提供有用的信息。但是，这些技术对于产生具有新骨架结构的活性分子来说并不是有效的。本研究的目的是开发利用3D-CG进行计算机药物设计的新方法和新软件。我们在药物受体理论的基础上开发了两个程序系统。一种是受体结构已知的情况。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，显示了该部位的物理和化学性质，用于实时估计药物与受体之间的相互作用能。通过这种方法，我们可以很容易地阐明构效关系和生物反应的机理，进而构建与受体药物结合部位相匹配的新结构。另一种是受体结构未知的情况。在3D-CG上叠加分子是比较多个活性化合物的最有效的方法之一。我们的方法是根据物理和化学性质叠加分子，而不是传统的原子位置。这种方法能够解释不同结构的化合物之间的构效关系。

Computer and three-dimensional computer graphic (3D-CG) are the powerful tools for rational drug design. They facilitate our understandings about 3-D structures and molecular recognition by biological macromolecules, as well as provide us logicality and quantitativity. Computer simulations such as molecular interactions, physical properties can give us useful informations for designing new active structures. But, these techniques are not efficient for generating active molecules with new skeletal structures. The aim of this research is developing new methods and softwares for computer drug design using 3D-CG. We have developed two program systems on the basis of drug-receptor theory. The one is for the case where the receptor structure is known. Various data calculated at each 3-D grid point inside the drug binding site of receptor, exhibiting physical and chemical properties of the site, are used for estimating the interaction energy between drug and receptor in realtime. By this method, we can easily elucidate structure-activity relationships and mechanisms of biological reactions, and furthermore construct new structures which can well fit to the drug binding site of the receptor. The other is for the case where the receptor structure is unknown. Superposing molecules on 3D-cg is one of the most efficient way of comparing plural active compounds. Our method is superposing molecules in terms of physical and chemical properties instead of atomic positions in the conventional way. This method enabled to explain the Structure-activity relationships between compound with quite different structures.