A Methodological Study Of De Novo Drug Design

De novo drug design is a molecular design method, according to binding site of enzyme with its physical and chemical properties, using the computer directly to design automatically novel molecular structures which are predicted to fit the active site of a target protein. De novo drug design and docking method are both called direct drug design methods, belong to the field of structure-based drug design. Docking approach is searching for structures which satisfy the structure requirements for activity from structural databases. This is a limitation, as it is confined to existing molecules. In contrast to the docking approach, the de novo design approach is constructing new structures directly into the active site so as to satisfy the requirements. It allows searching over a larger conformational space, as the potential lead compound is built adaptively to best fit the site, and therefore is not limited to a set of pre-existing database conformations. Since them, we have developed a method for generating a wide variety of new ligand structures automatically based on the 3D structures receptor.1. Analysis and establishment of fragment database for drug design Fragment library design is a difficult but important project for de novo drug design which builds up ligands, using the library of organic fragments. In order to better design the efficient fragment in drug design, we look in detail at the common features present in drug molecules, using shape description methods to analyze the MDDR database. Here we focus our mind on the MDDR database because of its a large diversity of compounds in a large number of therapeutic areas. A quick way of mining this structure data is to separate the substructures of each drug molecule into ring, link chain and side chain. Based on one strategy with considering both atom type and bond order to match molecular substructures, there are 134,856 known drugs analyzed. For our program we have set up three fragment libraries (a framework library, -a group library and a linker library) which can cover possible substructure in known drugs as widely as possible. There are 13,574 fragments in the framework library, 34,244 fragments in the group library, and 8,051 fragments in the linker library.2. Design and development of interactive system of De Novo drug design Using C++ programming language, we have developed a new program, called InterD2, which runs on Windows workstations and takes advantage of three fragments library to design molecules. Using grid analysis method, the...