The two-domain dipeptidylcarboxypeptidase Angiotensin-I-converting enzyme (EC
3.4.15.1; ACE) plays an important physiological role in blood pressure regulation via the reninangiotensin
and kallikrein-kinin systems by converting angiotensin I to the potent vasoconstrictor angiotensin
II, and by cleaving a number of other substrates including the vasodilator bradykinin and the
anti-inflammatory peptide N-acetyl-SDKP. Therefore, the design of ACE inhibitors is within the priorities
of modern medical sciences for treating hypertension, heart failures, myocardial infarction, and
other related diseases. Despite the success of ACE inhibitors for the treatment of hypertension and
congestive heart failure, they have some adverse effects, which could be attenuated by selective domain
inhibition. Crystal structures of both ACE domains (nACE and cACE) reported over the last decades
could facilitate the rational drug design of selective inhibitors. In this review, we refer to the history
of the discovery of ACE inhibitors, which has been strongly related to the development of molecular
modeling methods. We stated that the design of novel selective ACE inhibitors is a challenge
for current researchers which requires a thorough understanding of the structure of both ACE domains
and the help of molecular modeling methodologies. Finally, we performed a theoretical design of potential
selective derivatives of trandolaprilat, a drug approved to treat critical conditions of hypertension,
to illustrate how to use molecular modeling methods such as de novo design, docking, Molecular
Dynamics (MD) simulations, and free energy calculations for creating novel potential drugs with specific
interactions inside nACE and cACE binding sites.
Replacement of the Transmembrane Anchor in Angiotensin I-converting Enzyme (ACE) with a Glycosylphosphatidylinositol Tail Affects Activation of the B2Bradykinin Receptor by ACE Inhibitors
