Mechanism of action
Captopril is the smallest orally active tight-binding peptide analogue inhibitor of angiotensin converting enzyme (ACE). The drug molecule makes a direct interaction with the catalytic Zn(2+) ion (distance, 2.32 Å) deep inside the channel at the active site (Figure 2 B), and is anchored at the central carbonyl group and the proline carboxylate group. The central carbonyl group (between the SH group and the terminal proline) is positioned by strong H-bonds from two histidines (His513, 2.69 Å; His353, 2.54 Å). Similarly, one oxygen of captopril's proline carboxylate group is held by interactions with Tyr520 (2.66 Å), Gln281 (3.1 Å), and Lys511 (2.73 Å). These interactions appear to be sufficient to act as a backstop, positioning the substrate molecule so that the carbon of the scissile bond can undergo nucleophilic attack. The other carboxylate oxygen of the proline carboxylate interacts with the surrounding water molecules. The zinc coordination by the free SH in captopril is in contrast to the interaction of a phenyl carboxylate (i.e. ester) group with the Zn(2+) ion in the newer ACE inhibitors, e.g. lisinopril and enalaprilat.
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Model options CPK > Binding site H-bonds, Figure 2 B view > Drug molecule Show within 8 Å
The binding of the antihypertensive drug captopril to human testicular angiotensin I-converting enzyme [PDB structure code 1UZF]
R. Natesh, S. L. U. Schwager, H. R. Evans, E. D. Sturrock and K. R. Acharya, Biochemistry, 2004, 43, 8718–8724 (doi:10.1021/bi049480n).