MOLECULAR MODELLING AND DRUG DESIGN BY COMPUTER

计算机分子建模和药物设计

• 批准号: 5201248
• 负责人: G W MILNE
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5201248
• 关键词: active sites; antiAIDS agent; antineoplastics; chemical binding; chemical information system; chemical structure function; computer simulation; drug design /synthesis /production; endopeptidases; enzyme inhibitors; enzyme structure; enzyme substrate; integrase; ligands; model design /development; protein kinase C; protein tyrosine kinase

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.

酶的三维结构分析和建模， 它们的配体正在研究中。有源模拟方法， 涉及药效团鉴定，使用药效团搜索 NCI DIS 3D数据库和分子建模来检查 酶上的配体已被证明是一种非常成功的方法， 表征活性位点和鉴定化学上新颖的配体 作为酶的抑制剂， 毒品 NCI DIS 3D数据库一个包含50万个3D结构的数据库， 建立了NCI DIS数据库，并于1994年发表了这项工作。那里 药物开发实验室对这个数据库很感兴趣 文件的非机密部分现在已经被 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 确定了药效团的酶。这些化合物通常可以 取代天然底物，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效用， 成功地通过LMC来识别蛋白激酶C、HIV 蛋白酶，HIV整合酶和各种其他酶的重要性， 癌症和艾滋病化疗。的调控域分析 蛋白激酶C已经完成。调节活性位点和 对接过程已被表征和准确定量 已经对不同配体的结合能进行了估计。 用HIV整合酶和蛋白酶进行了同样的程序 以及酪氨酸激酶的SH 2结构域和调蛋白- erbB 3和erbB 4的结合位点。