STRUCTURE-BASED DRUG DESIGN OF A NOVEL SERIES OF HUMAN CATHEPSIN D INHIBITORS. Angela Y. Lee, Pavel Majer, Sergei V. Gulnik, Jack Collins, Abelardo M. Silva, Narayana T. Bhat and John W. Erickson, Structural Biochemistry Program, SAIC-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201

Cathepsin D (Cat D) is a lysosomal aspartic protease implicated in many aspects of pathology such as cancer and Alzheimer disease, thus representing a novel target of therapeutic importance. Development of specific and bioavailable Cat O inhibitors would aid in delineating its role in normal and disease states. Based on our recently solved X-ray structures of human Cat D and its complex with pepstatin A, a new series of inhibitors for Cat D have been designed, synthesized and kinetically characterized. In our attempt to better understand their modes of binding and to aid in our future design, crystallographic studies of human Cat D complexed with some of these inhibitors were carried out. The crystal structure of a complex with a linear statine-based compound will be compared with that of a related cyclic analog, as well as with the model structures.