Inhibitory Binding of Angiotensin Converting Enzyme Inhibitors with Carbonic Anhydrase III
- PDF / 868,217 Bytes
- 8 Pages / 595.276 x 790.866 pts Page_size
- 17 Downloads / 191 Views
ORIGINAL
Inhibitory Binding of Angiotensin Converting Enzyme Inhibitors with Carbonic Anhydrase III Noor el‑huda Kh. Daoud1 · Muhammed Alzweiri2 Received: 2 July 2020 / Revised: 30 September 2020 / Accepted: 3 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Both angiotensin converting enzyme (ACE) and carbonic anhydrase III (CAIII) are zinc-containing enzymes. Interestingly, blocking of the both enzymes is attributed with clinically significant outcomes against hyperlipidemia and obesity. An optimized in-vitro screening approach based on HPLC–size exclusion chromatography was adopted to study the angiotensin converting enzyme inhibitors (ACEIs) affinity against CAIII enzyme. Series of concentrations of the enzyme were injected in the column with a mobile phase containing one of ACEIs in each time. The affinity of the ACEIs toward CAIII was characterized by vacancy (negative) peak whose intensity representing the fraction of the drug bound with CAIII. To explore whether the binding is within the binding site or just a promiscuous binding, exact procedure was repeated with apo-protein part of CAIII. Furthermore, an esterase activity of CAIII was performed to determine if the binding with ACEIs is excitatory or inhibitory. It has been found that ACEIs have real in-vitro inhibitory effects against CAIII at a micro-molar level. The chromatographic study revealed that the ionized carboxylate groups are essential for binding with Zn+2 ion in the enzyme active site. Among the four tested ACEIs, captopril, ramipril, enalapril, and lisinopril, captopril was found to be the most potent inhibitor with Ki = 12.1 μM, while lisinopril is the least potent one with Ki = 25.3 μM. This finding might open the door for further investigation to optimize ACEIs as lead compounds for the discovery and development of selective and potent CAIII inhibitors. Keywords Carbonic anhydrase III · Angiotensin converting enzyme inhibitors (ACEIs) · Hypolipidemic effect · Hummal– Dryer method (HDM) · Size exclusion chromatography
Introduction Since 1990s, attention and focus have been started on the angiotensin converting enzyme inhibitors (ACEIs) in relation to the controlling mechanism against hyperlipidemia and atherosclerosis lesion. Recent clinical studies suggested that ACEIs’ drugs are magic bullets against atherosclerosis with no cut-off evidence for the underlying mechanism. * Noor el‑huda Kh. Daoud [email protected]; [email protected]
Muhammed Alzweiri [email protected]; [email protected]
1
Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, The Hashemite University, P.O box 330127, Zarqa 13133, Jordan
Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan
2
Several animal clinical studies reported that captopril with a dose of 25–50 mg/kg/day decreased early atherosclerosis; also, the formed atheroma contains fewer macrophage cells with relatively dominant connective tissue [1–4]. Others r
Data Loading...
