Abstract

A structural thermodynamic approach to the design of aspartic protease inhibitors is proposed. The energy of binding of small peptides is now well characterized. This information may be used in the rational design of peptidomimetic inhibitors of medically relevant aspartic proteases such as HIV protease. This work involves the use of structural thermodynamic algorithms developed at the center used in conjunction with docking algorithms in order to design peptides that are predicted to have the highest affinity for the protease. These predictions are then compared to experimental binding data obtained on the center calorimeters.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR004328-09
Application #
5224865
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
1996
Total Cost
Indirect Cost

  Publications

Jaganaman, Sunil; Pinto, Alex; Tarasev, Michael et al. (2007) High levels of expression of the iron-sulfur proteins phthalate dioxygenase and phthalate dioxygenase reductase in Escherichia coli. Protein Expr Purif 52:273-9
Todd, M J; Gomez, J (2001) Enzyme kinetics determined using calorimetry: a general assay for enzyme activity? Anal Biochem 296:179-87
Karantza, V; Freire, E; Moudrianakis, E N (2001) Thermodynamic studies of the core histones: stability of the octamer subunits is not altered by removal of their terminal domains. Biochemistry 40:13114-23
Griko, Y V; Remeta, D P (1999) Energetics of solvent and ligand-induced conformational changes in alpha-lactalbumin. Protein Sci 8:554-61
Lee, R T; Gabius, H J; Lee, Y C (1998) Thermodynamic parameters of the interaction of Urtica dioica agglutinin with N-acetylglucosamine and its oligomers. Glycoconj J 15:649-55
Zakharov, S D; Lindeberg, M; Griko, Y et al. (1998) Membrane-bound state of the colicin E1 channel domain as an extended two-dimensional helical array. Proc Natl Acad Sci U S A 95:4282-7
Luque, I; Todd, M J; Gomez, J et al. (1998) Molecular basis of resistance to HIV-1 protease inhibition: a plausible hypothesis. Biochemistry 37:5791-7
Chu, V; Freitag, S; Le Trong, I et al. (1998) Thermodynamic and structural consequences of flexible loop deletion by circular permutation in the streptavidin-biotin system. Protein Sci 7:848-59
Luque, I; Freire, E (1998) Structure-based prediction of binding affinities and molecular design of peptide ligands. Methods Enzymol 295:100-27
Luque, I; Gomez, J; Semo, N et al. (1998) Structure-based thermodynamic design of peptide ligands: application to peptide inhibitors of the aspartic protease endothiapepsin. Proteins 30:74-85

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