Renin inhibitors: a search for principles of design.

Principles for the design of renin inhibitors were examined by utilizing a three-dimensional model of the enzyme with inhibitory peptides in its catalytic site. Optimal conformations were subjected to energy minimization by the computer program CHARMM. The results were then compared with the inhibitory potencies of these peptides as assessed by an in vitro renin assay. The results of the modeling study and enzymatic assay were generally congruent, showing that residues at the P5, P4 and P3 positions contributed importantly to binding, that an acetyl group can replace Pro-His at the P5, P6 position, that the lesser potency of AHPPA-containing as compared with statine-containing peptides may be related to the better fit into the S1 subsite of an isobutyl as opposed to a benzyl side chain, that histidine in the P2 position forms an essential hydrogen bond with residue 230 (which cannot be formed by another basic residue), and that there is a general correlation between inhibitory potency and calculated energy of interaction as deduced from the model. Major determinants of energy of binding are conformational strain and electrostatic interaction.