In vitro and in silico interactions of antiulcer, glucocorticoids and urological drugs on human carbonic anhydrase I and II isozymes

Abstract

Carbonic anhydrases (CAs, Enzyme Commission 4.2.1.1) convert carbon dioxide to bicarbonate in metabolism and use Zn 2+ ions as a cofactor for their catalytic activity. The activators or inhibitors of CA-I and CA-II, which are the most abundant CA isozymes in erythrocytes, have pharmacological applications in medicine. So, investigation of drug-protein interaction of these isozymes is significant. On this basis, the objective of this study was to clarify the primer effects of widely used drugs on the activity of human CA-I and CA-II enzymes and elucidate the inhibition mechanism through molecular docking studies. For this aim isozymes were purified from human erythrocytes by affinity chromatography technique. Then inhibition profiles of antiulcer, glucocorticoids, and urological drugs were investigated. As a result, while budesonide had the highest inhibitory potency on hydratase activity of hCA-I with the IC 50 of 0.08 mM, levofloxacin showed the highest inhibition effect on hCA-II with the IC 50 of 0.886 mM. The most effective inhibitor on the esterase activity of isozymes was found as fluticasone propionate with the K i values of 0.0365 � 0.016 mM and 0.054 � 0.018 mM respectively. However, by molecular docking study, it was estimated that budesonide showed maximum inhibition potency for both isozymes with the free binding energy of −7.58 and −6.97 kcal/mol, respectively. Consequently, it was observed that some of the drugs studied did not show any inhibitory effect. Drug-enzyme interactions were also estimated by molecular docking. This study could contribute to the discovery of new drug candidates and as well as target proteins. K E Y W O R D Sdrug-protein interaction, inhibition, isozyme purification, molecular docking | INTRODUCTIONCarbon dioxide formed due to the oxidation metabolism of nutrients (glucose, fatty acid, amino acids) must be rapidly converted into water-soluble form to not damage cellular organelles and membranes. The conversion of CO 2 and bicarbonate to each other has a role in the binding of oxygen and its release into the blood.Thus, the binding of oxygen by hemoglobin is greatly affected by CO 2 concentration and pH. It takes place 10 4 -10 6 times faster in the catalysis of carbonic anhydrase (CA). Hemoglobin transports 20% of the total H + and CO 2 , formed in the tissues, to the lungs and kidneys. The binding of H + and CO 2 is inversely proportional to the binding of oxygen. Since H + and CO 2 bind at relatively low pH and high CO 2 concentrations in peripheral tissues, the affinity of

2‐Amino thiazole derivatives as inhibitors of some metabolic enzymes: An in vitro and in silico study

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“…32 While Tacrine (TAC) was used as standart inhibitor of cholinesterases, acetazolamide (AZA) was used as standard inhibitor of hCA isozymes. 33,34…”

4‐Furfuryloxymethyl‐1,2,3‐triazol‐1‐yl‐acetohydrazide Hybrids as Cholinesterase and Carbonic Anhydrase Inhibitors: Synthesis, Characterization and Comprehensive Biological Activity Studies

“…One enzyme unit is defined as the amount of enzyme that hydrolyzes 1 μmol of 4nitrophenyl acetate to 4-nitrophenol in 1 minute. [56,59]…”

Synthesis, Biological Evaluation, and In Silico Studies of Novel Coumarin-Based 4H,5H-pyrano[3,2-c]chromenes as Potent β-Glucuronidase and Carbonic Anhydrase Inhibitors

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“…16,17 Carbonic anhydrase (CA) isoenzymes are pervasive members of metalloenzymes with a Zn(II) ion metallic core at the active center of the enzyme. 18,19 They are prevalent in all organisms where they are engaged in the reversible catalysis of hydration of CO 2 to (HCO 3 −1…”