STRUCTURE-BASED DESIGN OF INHIBITORS FOR COMPLEMENT PROTEIN D

COMPLEMENT PROTEIN FACTOR D PLAYS AN IMPORTANT ROLE IN THE ALTERNATIVE PATHWAY OF THE COMPLEMENT SYSTEM. INHIBITORS FOR FACTOR D HAVE POTENTIAL APPLICATION IN THE TREATMENT OF ADULT RESPIRATORY SYNDROME (ARDS) AND AUTOIMMUNE DISEASES SUCH A RHEUMATOID ARTHRITIS. THE PHASE I OBJECTIVE IS TO DETERMINE THE THREE-DIMENSIONAL STRUCTURE OF FACTOR D BY X-RAY CRYSTALLOGRAPHIC METHODS. DIFFRACTION DATA FOR NATIVE CRYSTALS AND TWO POTENTIAL HEAVY ATOM DERIVATIVES ARE IN HAND. A MOLECULAR REPLACEMENT SOLUTION HAS BEEN OBTAINED USING THE STRUCTURE OF THE HOMOLOGOUS SERINE PROTEASE, RAT MAST CELL PROTEASE. THIS MODEL HAS BEEN REFINED TO AN R-VALUE OF 0.21, USING XPLOR. THE INVESTIGATORS PLAN TO IMPROVE THE INITIAL MAP BY USING PHASE COMBINATION (OF THE MOLECULAR REPLACEMENT AND MULTIPLE ISOMORPHOUS REPLACEMENT PHASES); BUILD THE FACTOR D MODEL; REFINETHE STRUCTURE AND CHARACTERIZE THE ACTIVE SITE TO UNDERSTAND THE MECHANISM OF ACTION. THE LONG TERM-TERM GOAL IN PHASE II IS TO DESIGN AND SYNTHESIZE SPECIFIC INHIBITORS FOR FACTOR D USING A STRUCTURE-BASED DRUG DESIGN PROCESS.