MOLECULAR MODELLING AND DRUG DESIGN BY COMPUTER

一个基础广泛的三维分析和建模程序

A broad-based program of analysis and modeling of three-dimensional structures and their use in drug design is in progress. This effort includes pharmacophore identification and analysis, 3D searching of the NCI database and modeling of the active sites in proteins. Modeling Studies Molecular models of structures of interest as chemotherapeutic agents are produced routinely using a variety of computer programs and the models produced have been compared to x-ray structures. Models have been generated of the active sites of various proteins and the mechanism of binding of substrates to these active sites is being studied. Protein Kinase C The pharmacophore of protein kinase C has been characterized in detail, and by searching the NCI 3D database, numerous new PKC activators have been discovered. The model is also used to refine the structures of known binders and so increase their affinity for the enzyme. Tyrosine Protein Kinase The SH2 binding site in several PTK proteins has been characterized and the definition of the putative pharmacophore has been completed. This has enabled searching of the 3D database for peptide and peptidomimetic compounds that can bind to this site and such searches are being carried out. Three-Dimensional Database Conversion of the NCI Database from 2D to 3D has been completed using both the CONCORD and Chem-X programs. A copy of the Chem-X database has been installed on both the DTP VAX and LMC workstations. The Chem-X search programs are running on these workstations and searches can now be done locally.