Cathepsin inhibitor design

Bromme., D. and Kaleta, J. (2002) Thiol-dependent cathepsins pathophysiological implications and recent advances in inhibitor design. Current Pharmaceutical Design, 8 (18), 1639-1658. 

Grabowska, U.B. et al. Recent developments in cathepsin K inhibitor design. Curr. Opin. Drug Discov. Devel. 

S. Sudarsanam, G. D. Virca, C. J. March, and S. Srinivasan, J. Comput.-Aided Mol. Design, 6, 223 (1992). An Approach to Computer-Aided Inhibitor Design Application to Cathepsin L. 

Cathepsin D. The design of inhibitors of the aspartyl protease cathepsin D started from a virtual library of peptide analogs that contained the typical hydroxyethylamine isoster for the cleavable peptide bond. As the availability of starting materials would have generated a library of about 1 billion compounds, virtual screening was applied to reduce this multitude of candidate structures to a reasonable number. The backbone of a peptide... 

When the target enzyme is difficult to obtain, related enzymes could be used to provide insights in the design of novel ligands. For example, papain was used to design a class of potent cathepsin K inhibitors [33] spanning both sides of the papain active site. However, fine-tuning these inhibitors to produce more potent ones required the use of the crystal structure of cathepsin K itself [34],... 

LaLonde JM, Zhao B, Smith WW, Janson CA, DesJarlais RL, Tomaszek TA, Carr TJ, Thompson SK, Oh HJ, Yamashita DS, Veber DF, Abdel-Meguid SS. Use of papain as a model for the structure-based design of cathepsin K inhibitors crystal structures of two papain-inhibitor complexes demonstrate binding to S -subsites. J Med Chem 1998 41 4567-4576. 

Fig. 5.9 Design of the chip-based enzyme ESI-MS assay. MS instrument Ion-trap mass spectrometer (LCQ Deca, Thermo Electron). I Sample components/inhibitors injected by flow injection or eluting from capillary HPLC column. E Infusion pump delivering the enzyme cathepsin B. S infusion pump delivering the substrate Z-FR-AMC. Micro-chip design Vrije Universiteit Amsterdam. Micro-chip production Micronit Microfluidics BV (Enschede, The Netherlands).

Case study structure-based design of cathepsin K inhibitors... 

Figure 17.3 Schematic representation of the design of the symmetric cathepsin K inhibitor diacylaminomethyl ketone (1,3-bis[[A/-[(phenylmethoxy)carbonyl]-L-leucyl]amino]-2-propanone), based on the crystal structures of papain bound to leupeptin (Leu-Leu-Arg-aldehyde) and to Cbz-Leu-Leu-Leu-aldehyde, and an example of its further optimization.

D. F. (1998). Stmcture-based design of cathepsin K inhibitors containing a benzyloxy-substituted benzoyl peptidomimetic. /. Med. Chem. 41,3923-3927. 

Veber, D. F. and Cummings, M. D. (2004). Structure-based design of cathepsin K inhibitors. In Protein Crystallography in Drug Discovery. Methods and Principles in Medicinal Chemistry, Babine, R. E. and Abdel-Meguid, S. S., eds, Vol. 20, Wiley-VCH, p. 127-146. 

Trifluoroethylamines can also be considered as metabolically stable amide iso-steres. A CF3 group can replace the C=0 of an amide and generates a metabolically stable, non-basic amine that maintains the excellent hydrogen bonding. This concept has been developed in the design of protease inhibitors (cathepsin K) (Fig. 18) [62]. 

One of the goals of synthetic medicinal chemistry is to design potent inilibitors of clinically important proteases. Elastase inhibitors may be useful for treatment of emphysema, pancreatitis, and arthritis,a/b while inhibitors of the angiotensinogen-converting enzyme or of renin (Box 22-D) can help control blood pressure. Inhibition of thrombin, factor Xa, or other blood clotting factors (Fig. 12-17) may prevent blood clots and inhibition of the cytosolic tryptase may provide a new treatment for asthma. Inhibition of the cysteine protease cathepsin K may help combat osteoporosis and inhibition of cysteine proteases of corona viruses may fight the common cold. Cysteine proteases of schistosomes are also targets for protease inhibitors.c... 

Ellman, Chem. Biol., 4, 297 (1997). Structure-Based Design and Combinatorial Chemistry Yield Low Nanomolar Inhibitors of Cathepsin D. 

Kick EK, Roe DC, Skillman AG, Liu G, Ewing TJA, Sun Y, Kuntz ID, Ellman JA, Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of Cathepsin D, Chemistry and Biology, 4 297-307, 1997. 

One goal in the design of an inhibitor is specificity. Often this is a considerable challenge since physiological systems contain a number of closely related proteases. For example, there are at least four chymo-trypsin-like enzymes in humans. These include pancreatic chymotrypsin, cathepsin G, and two mast cell proteases (the human enzymes have not been characterized yet, but two are found in rats). All of these enzymes... 

We tested combiBUILD by using it to help design inhibitors for cathepsin D. Cathepsin D is an aspartyl protease whose structure has been solved with the inhibitor pepstatin. It is implicated in several disease processes including Alzheimer s amyloid plaque formation and breast cancer metastasis. Our goal was to design a small library of 1000 compounds of possible inhibitors to Cathepsin D. 

Top Four-dimensional library design [94] (left) utilized by SmithKIine Beecham for generating cathepsin K inhibitors (right). 

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