Conformational analysis of aliskiren, a potent renin inhibitor, using high-resolution nuclear magnetic resonance and molecular dynamics simulations

Aliskiren is a nonpeptide antihypertensive drug that potently inhibits the human enzyme renin in vitro and in vivo. Many clinical trials have shown the efficacy of aliskiren to lower blood pressure in correlation with other antihypertensive agents. In this report, the conformational behavior of aliskiren is studied in water, trifluoroethanol, and dimethylformamide solutions by means of 2D-NMR spectroscopy and molecular dynamics simulations. The stereochemical characteristics of aliskiren in different solutions, in combination with the previously published crystal structure of the renin-aliskiren complex have been investigated. The aim of this study was to explore the conformational behavior of this first successful renin inhibitor in relation to its environment. In aqueous solution, aliskiren adapts a U-shape conformation, whereas in DMF, the molecule is basically endowed with an "extended" conformation, which has more similarities to the one bound to the receptor.