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.
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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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The authors are thankful to Dr. Haneen Khaled for her teaching on NKH how to establish chromatography system.
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The work was supported by the University of Jordan represented by the deanship of academic research (financial grant number: 16287).
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Daoud, N.eh.K., Alzweiri, M. Inhibitory Binding of Angiotensin Converting Enzyme Inhibitors with Carbonic Anhydrase III. Chromatographia 83, 1517–1524 (2020). https://doi.org/10.1007/s10337-020-03973-1
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DOI: https://doi.org/10.1007/s10337-020-03973-1