Shape-based fragment assembly in de novo drug design

The INVENTON paradigm starts with describing the objectives and criteria of a molecular design problem by a chemist. INVENTON then takes over and proceeds to invent molecules that achieve the objectives and satisfy the criteria. INVENTON works unsupervised and determines its own course for execution. After the invention is done, the chemist can analyze the structures and filter out the interesting ones for further analysis. 1; Following the same paradigm created by Wipke and Pitman in INVENTON , this thesis introduced a novel de novo drug design approach which assembles molecular fragments solely based on shape complementarity between the fragments and the protein active site. This shape-based fragment assembly process (SPASM) perceives only the shape of the active site, which is the minimum requirement of the protein active site. A chemist can give the termination criteria such as total number of structures to be invented and the minimum volume of each structure. SPASM determines its own course and assembles the shape complementary structures unsupervised.; SPASM has been applied to design inhibitors for two unrelated enzymes (cyclooxy-genase and Pneumocystis carinii dihydrofolate reductase). SPASM was able to generate high yield of novel shape complementary structures for both enzymes. Several new data mining methods were also introduced to study the SPASM database, to compare the FASM and SPASM databases, and to filter out interesting candidates.; As the new addition to the INVENTON paradigm, SPASM explores the novel chemical space that contains shape complementary structures to a protein active site. These novel structures may open the eyes of the chemist who otherwise biasedly searches the lead compound based on his/her experience. However we, as the chemists, are not being replaced but rather being promoted by the computer since we teach the computer how to be creative and we evaluate the creative work done by the computer.