MOLECULAR MODELLING AND DRUG DESIGN BY COMPUTER

酶的三维结构分析和建模

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.