MOLECULAR MODELLING AND DRUG DESIGN BY COMPUTER

酶和酶的三维结构分析与建模 他们的配体正在研究中。有源模拟方法，它 涉及药效团的识别，利用药效团进行搜索 NCI DIS 3D数据库和分子建模以检查 事实证明，在酶上配基是一种非常成功的方法 活性中心的表征和新的化学配体的鉴定 它们作为酶的抑制剂，因此代表着新的铅 毒品。 NCI DIS 3D数据库包含500,000个对应于 建立了NCI DIS数据库，并于1994年发表了这项工作。那里 对药物开发实验室的这个数据库非常感兴趣 而文件中的非机密部分现在已经 在互联网上以ftp文件的形式提供。 药效团搜索许多药效团搜索已经完成 在3D数据库中。这样的搜索导致化学物质可以结合到 定义了其药效团的酶。这类化合物通常可以 取代一种天然底物，因此具有作为药剂的潜力。 这种在3D数据库中搜索特定药效团的技术 似乎在药物化学中具有普遍用途，并已被用于 LMC成功地识别了蛋白激酶C、HIV的抑制剂 蛋白水解酶、HIV整合酶和其他各种具有重要意义的酶 癌症和艾滋病化疗。对《公约》监管范围的分析 蛋白激酶C已经完成。监管活动站点和 对接过程进行了表征和准确的量化 对不同配体的结合能进行了估算。 对HIV整合酶和蛋白酶也进行了同样的处理 以及酪氨酸激酶的SH2结构域和海藻糖蛋白- ErBB3和ErBB4的结合部位。

Analysis and modeling of three-dimensional structures of enzymes and their ligands is being studied. The active analog approach, which involves pharmacophore identification, use of the pharmacophore to search the NCI DIS 3D database and molecular modeling to examine the docking of a ligand onto the enzyme has proved to be a very successful means of characterizing active sites and of identifying chemically novel ligands which serve as inhibitors of the enzyme and thus represent new lead drugs. NCI DIS 3D Database A database of 500,000 3D structures corresponding to the NCI DIS database was built and this work was published in 1994. There is great interest in this database in drug development laboratories around the world and the non-confidential part of the file has now been made available as an FTP file on the Internet. Pharmacophore Searching Many pharmacophore searches have been completed in the 3D database. Such searches lead to chemicals which can bind to the enzyme whose pharmacophore was defined. Such compounds often can displace a natural substrate and thus have potential as medicinal agents. This technique of searching in a 3D database for specific pharmacophores appears to have general utility in medicinal chemistry and has been used successfully by the LMC to identify inhibitors of protein kinase C, HIV protease, HIV integrase and various other enzymes of significance in cancer and AIDS chemotherapy. An analysis of the regulatory domain of protein kinase C has been completed. The regulatory active site and the docking process have been characterized and accurate quantitative estimates of the binding energies of different ligands have been made. The same procedure has been carried out with HIV integrase and protease as well as with the SH2 domain of tyrosine kinase and the heregulin- binding sites of erbB3 and erbB4.