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Structure-Based Subsite Specificity Mapping of Human Cathepsin D Using Statine-Based Inhibitors

  1. Author:
    Majer, P.
    Collins, J. R.
    Gulnik, S. V.
    Erickson, J. W.

  2. Author Address

    Majer P NCI FREDERICK CANC RES & DEV CTR STRUCT BIOCHEM PROGRAM SAIC FREDERICK POB B BLDG322 FREDERICK, MD 21702 USA
    1. Year: 1997
  2. Journal: Protein Science
    1. 6
    2. 7
    3. Pages: 1458-1466
  4. Type of Article: Article
  1. Abstract:

    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 2:263-276). 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. [References: 20]

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