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

Physiological and pathological roles of cysteine proteases make them import ant tar gets for inhibitor development. Although highly potent inhibitors o f this group of enzymes are known, their major drawback is a lack of suffic ient specificity. Two cysteine protease covalent inhibitors, viz. (i) Z-RL- deoxo-V-peptide-epoxysuccinyl hybrid, and (ii) Z-RLVG-methyl-, have been de veloped and modeled in the catalytic pocket of papain, an archetypal thiol protease. A number of configurations have been generated and relaxed for ea ch system using the AMBER force field. The catalytic pockets S-3 and S-4 ap pear rather elusive in view of the observed inhibitors' flexibility. This s uggest rather limited chances for the development of selective structure-ba sed inhibitors of thiol proteases, designed to exploit differences in the s tructure of catalytic pockets of various members of this family.