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Protein Science, Vol 6, Issue 7 1458-1466, Copyright © 1997 by Cold Spring Harbor Laboratory Press

ARTICLE

Structure-based subsite specificity mapping of human cathepsin D using statine-based inhibitors

P. MAJER, J. R. COLLINS, S. V. GULNIK and J. W. ERICKSON
Structural Biochemistry Program, SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201

Human cathepsin D is a lysosomal aspartic protease that has been implicated in breast cancer metastasis and Alzheimer's disease. Based on a crystal structure of a human cathepsin D-pepstatin A complex, a series of statine-containing inhibitors was designed, synthesized, and tested for inhibitory activity toward the enzyme in vitro. The compounds were modified systematically at individual positions (P(4), P(3), P(2), P(1), and P'(2)) with the aim of mapping the cathepsin D subsite preferences. The experimentally obtained SAR data were correlated on the basis of molecular modeling. Side-chain preferences for the peptidomimetic inhibitors differed from those found previously using peptide substrates (Scarborough PE et al., 1993, Protein Sci 2:264-276). In addition, the effects of single side-chain modifications were often nonadditive. Structure-activity relationships, modeling, and thermodynamic analysis indicated that entropy plays a major stabilizing role in inhibitor binding to cathepsin D.
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Copyright © 1997 by The Protein Society.