ACE Inhibitors Drug Design - Discovery of 2 Active Sites: C-domain and N-domain

Discovery of 2 Active Sites: C-domain and N-domain

Most of the ACE inhibitors on the market today are non-selective towards the two active sites of ACE because their binding to the enzyme is based mostly on the strong interaction between the zinc atom in the enzyme and the strong chelating group on the inhibitor. The resolution of the 3D structure of germinal ACE, which has only one active site that corresponds with C-domain of the somatic ACE, offers a structural framework for structure-based design approach. Although N- and C-domain have comparable rates in vitro of ACE hydrolyzing, it seems like that in vivo the C-domain is mainly responsible for regulating blood pressure. This indicates that C-domain selective inhibitors could have similar profile to that of a current non-selective inhibitors. Angiotensin I is mainly hydrolyzed by the C-domain in vivo but bradykinin is hydrolyzed by both active sites. Thus, by developing a C-domain selective inhibitor would permit some degradation of bradykinin by the N-domain and this degradation could be enough to prevent accumulation of excess bradykinin which has been observed during attacks of angioedema. C-domain selective inhibition could possibly result in specialized control of blood pressure with less vasodilator-related adverse effects. N-domain selective inhibitors on the other hand give the possibility of opening up novel therapeutic areas. Apparently, the N-domain doesn’t have a big role in controlling blood pressure but it seems to be the principal metabolizing enzyme for AcSDKP, a natural haemoregulatory hormone.