Abstract
Angiotensin-converting enzyme (ACE) has a critical role in cardiovascular function by cleaving the carboxy terminal His-Leu dipeptide from angiotensin I to produce a potent vasopressor octapeptide, angiotensin II. Inhibitors of ACE are a first line of therapy for hypertension, heart failure, myocardial infarction and diabetic nephropathy. Notably, these inhibitors were developed without knowledge of the structure of human ACE, but were instead designed on the basis of an assumed mechanistic homology with carboxypeptidase A. Here we present the X-ray structure of human testicular ACE and its complex with one of the most widely used inhibitors, lisinopril (N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline; also known as Prinivil or Zestril), at 2.0 A resolution. Analysis of the three-dimensional structure of ACE shows that it bears little similarity to that of carboxypeptidase A, but instead resembles neurolysin and Pyrococcus furiosus carboxypeptidase--zinc metallopeptidases with no detectable sequence similarity to ACE. The structure provides an opportunity to design domain-selective ACE inhibitors that may exhibit new pharmacological profiles.
Highlights
Inhibitors of angiotensinconverting enzyme (ACE) are a group of chemical substances, used directly for treatment of hypertension and chronic heart failure
Using Bioeurica’ program, in the process of molecular dynamics simulation, the lisinopril molecule was placed into the active center of the ACE
According to the results of molecular dynamics simulation with the charges corresponding to basis set 6-31G*, lisinopril does not lose its conformational stability in the active center of the enzyme
Summary
Inhibitors of angiotensinconverting enzyme (ACE) are a group of chemical substances, used directly for treatment of hypertension and chronic heart failure. The principle of action of ACE inhibitors is based on blocking the conversion of angiotensin I into angiotensin II, which mediates vasodilation. This reduces the secretion of aldosterone by adrenal cortex and increases concentration of bradykinin by decreasing its inactivation by the enzyme (ACE). At the present stage of hypertension treatment angiotensin converting enzyme inhibitors are widely used. When they are taken, a coronary, renal, muscle and cerebral blood circulation becomes normal, which is an important advantage of this group of drugs. Angiotensin-converting-enzyme inhibitors decrease total peripheral vascular resistance, post - and preload on the myocardium, reduce the incidence of arrhythmias, improve a cardiac function in the diastolic phase
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