Theoretical studies of binding modes of two covalent inhibitors of cysteine proteases.

• Authors: Piotr Drabik , Ewa Politowska , Cezary Czaplewski , Franciszek Kasprzykowski , Leszek Łankiewicz , Jerzy Ciarkowski
• Languages of publication: EN

Abstracts

EN

Physiological and pathological roles of cysteine proteases make them important targets for inhibitor development. Although highly potent inhibitors of this group of enzymes are known, their major drawback is a lack of sufficient specificity. Two cysteine protease covalent inhibitors, viz. (i) Z-RL-deoxo-V-peptide-epoxysuccinyl hybrid, and (ii) Z-RLVG-methyl-, have been developed and modeled in the catalytic pocket of papain, an archetypal thiol protease. A number of configurations have been generated and relaxed for each system using the AMBER force field. The catalytic pockets S3 and S4 appear rather elusive in view of the observed inhibitors' flexibility. This suggest rather limited chances for the development of selective structure-based inhibitors of thiol proteases, designed to exploit differences in the structure of catalytic pockets of various members of this family.

Keywords

EN

cysteine proteases; covalent protease inhibitors; constrained simulated annealing; papain; molecular dynamics

• Journal: Acta Biochimica Polonica
• Year: 2000
• Volume: 47
• Issue: 4
• Pages: 1061-1066

Dates

published

2000

received

2000-03-13

revised

2000-07-24

accepted

2000-11-9

Contributors

author

Piotr Drabik

• Department of Public Health, University School of Physical Education, Gdańsk, Poland

author

Ewa Politowska

• Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland

author

Cezary Czaplewski

• Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland

author

Franciszek Kasprzykowski

• Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland

author

Leszek Łankiewicz

• Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland

author

Jerzy Ciarkowski

• Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland

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