CRYSTALLOGRAPHIC STUDIES ON THE BINDING MODES OF P-2-P-3 BUTANEDIAMIDE RENIN INHIBITORS

The binding modes of three peptidomimetic P-2-P-3 butanediamide renin inhibitors have been determined by x-ray crystallography. The inhibito rs are bound with their backbones in an extended conformation, and the ir side chains occupying the S-5 to S-1' pockets. A (2-amino-4-thiazol yl)methyl side chain at the P-2 position shows stronger hydrogen-bondi ng and van der Waals interactions with renin than the His side chain, which is present in the natural substrate. The ACHPA-gamma-lactam tran sition state analog has similar interactions with renin as the dihydro xyethylene transition state analog.