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Carbonic anhydrase II (CA II) is crucial for maintaining homeostasis in several processes, including respiration, lipogenesis, gluconeogenesis, calcification, bone resorption, and electrolyte balance. It is a pivotal druggable target which is implicated in glaucoma, renal, gastric, and pancreatic carcinomas, as well as in malignant brain tumours. Therefore, to identify new CA II (bovine) inhibitors, the current study was designed to synthesize a library of 20 new triazole-linked hydrazones (6a-t). All compounds were characterized by using spectroscopic techniques such as NMR and mass spectrometry. The in-vitro evaluation resulted in impressive inhibitory capability against CA II with IC50 values ranging from 9.10 ± 0.26-48.26 ± 1.30 µM. Among all derivatives, compounds 6a, 6b, 6d, 6k-6m, 6q, 6s and 6t exhibited potent inhibitory potential with 6t deemed as the most active inhibitor. Additionally, kinetic study of the hybrid 6t revealed concentration dependent type of inhibition with Ki value 7.24 ± 0.0086 µM. Furthermore, molecular docking of 6t correlates well with the kinetic analysis. The in-silico ADMET indicated that most of the synthesized compounds have properties conducive to drug development.

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A small library of 79 substituted phenylsulfonamidoalkyl sulfamates, 1b-79b, was synthesized starting from arylsulfonyl chlorides and amino alcohols with different numbers of methylene groups between the hydroxyl and amino moieties yielding intermediates 1a-79a, followed by the reaction of the latter with sulfamoyl chloride. All compounds were screened for their inhibitory activity on bovine carbonic anhydrase II. Compounds 1a-79a showed no inhibition of the enzyme, in contrast to sulfamates 1b-79b. Thus, the inhibitory potential of compounds 1b-79b towards this enzyme depends on the substituent and the substitution pattern of the phenyl group as well as the length of the spacer. Bulkier substituents in the para position proved to be better for inhibiting CAII than compounds with the same substituent in the meta or ortho position. For many substitution patterns, compounds with shorter spacer lengths were superior to those with long chain spacers. Compounds with shorter spacer lengths performed better than those with longer chain spacers for a variety of substitution patterns. The most active compound held inhibition constant as low as Ki = 0.67 µM (for 49b) and a tert-butyl substituent in para position and acted as a competitive inhibitor of the enzyme.

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A four-leaf water clover (Marsilea species) has been reported to exhibit various biological activities. In the present study, we aimed to evaluate 23 selected constituents of a four-leaf water clover (Marsilea species) as potent inhibitory agents of human acetyl cholinesterase (hAchE), carbonic anhydrase II (hCA-II), and protein tyrosine phosphatase 1B (hPTP-1B) using an in silico method. The 23 selected constituents of the four-leaf water clover (Marsilea species) were studied on the docking behavior of hAchE, hCA-II, and hPTP-1B by using the Webina docking method. In addition to docking, toxicity analysis was also performed using the pkCSM web server. Toxicity analysis has shown that 10 ligands (44%) of the four-leaf water clover (Marsilea species) were predicted to have hERG II (human ether-a-go-go-related gene) inhibition activity. The docking analysis showed that marsilin has exhibited the maximum binding energy (-11.3 kcal/mol) with the hAchE, whereas it fails to dock with both the target enzymes (hCA-II and hPTP-1B). Thus, the present find provides a new understanding about the 23 selected ligands of the four-leaf water clover (Marsilea species) as potent inhibitory agents of human acetyl cholinesterase (hAchE), carbonic anhydrase II (hCA-II), and protein tyrosine phosphatase 1B (hPTP-1B).

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Human carbonic anhydrases (hCAs) play a central role in various physiological processes in the human body. HCAs catalyze the reversible hydration of CO2 into HCO3-, and hence maintains the fluid and pH balance. Overexpression of CA II is associated with diseases, such as glaucoma, and epilepsy. Therefore, CAs are important clinical targets and inhibition of different isoforms, especially hCA II is used in treatment of glaucoma, altitude sickness, and epilepsy. Therapeutically used CA inhibitors (CAI) are sulfonamide-based, such as acetazolamide, dichlorphenamide, methazolamide, ethoxzolamide, etc. However, they exhibit several undesirable effects such as numbness, tingling of extremities, malaise, metallic taste, fatigue, renal calculi, and metabolic acidosis. Therefore, there is an urgent need to identify safe and effective inhibitors of the hCAs. In this study, different phenyl boronic acids 1-5 were evaluated against bovine (bCA II) and hCA II. Among all, compound 1 (4-acetylphenyl boronic acid) was found to be active against bCAII and hCA II with IC50 values of 246 ± 0.48 and 281.40 ± 2.8 µM, respectively, while the remaining compounds were found in-active. Compound 1 was identified as competitive inhibitor of hCA II enzyme (Ki = 283.7 ± 0.002 µM). Additionally, compound 1 was found to be non-toxic against BJ Human fibroblast cell line. The X-ray crystal structure for hCA II in-complex with compound 1 was evaluated to a resolution of 2.6 Å. In fact, this the first structural analysis of a phenyl boron-based inhibitor bound to hCA II, allowing an additional structure-activity analysis of the compounds. Compound 1 was found to be directly bound in the active site of hCA II by interacting with His94, His119, and Thr199 residues. In addition, a bond of 3.11 Å between the zinc ion and coordinated boron atom of the boronic acid moiety of compound 1 was also observed, contributing to binding affinity of compound 1 for hCA II. PDB ID: 8IGF.

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Various carbonic anhydrase (CA) enzyme isoforms are known today. In addition to the use of CA inhibitors as diuretics, antiepileptics and antiglaucoma agents, the inhibition of other specific isoforms of CA was reported to have clinical benefits in cancers. In this study, two groups of 1,3,4-thiadiazole derivatives were designed and synthesized to act as human CA I and II (hCA I and hCA II) inhibitors. The activities of these compounds were tested in vitro and evaluated in silico studies. The activity of the synthesized compounds was also tested against acetylcholinesterase (AChE) to evaluate the relation of the newly designed structures to the activity against AChE. The synthesized compounds were analyzed by 1H NMR,13C NMR and high-resolution mass spectroscopy (HRMS). The results displayed a better activity of all the synthesized compounds against hCA I than that of the commonly used standard drug, Acetazolamide (AAZ). The compounds also showed better activity against hCA II, except for compounds 5b and 6b. Only compounds 6a and 6c showed superior activity against AChE compared to the standard agent, tacrine (THA). In silico studies, including absorption, distribution, metabolism and excretion (ADME) and drug-likeness evaluation, molecular docking, molecular dynamic simulations (MDSs) and density functional theory (DFT) calculations, were compatible with the in vitro results and presented details regarding the structure-activity relationship.Communicated by Ramaswamy H. Sarma.

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Background Urtica dioica (Stinging nettle)has been reported to exhibit various pharmacological activities. In the present study, we aimed to evaluate 24 selected constituents of U. dioica as potent inhibitory agents of human carbonic anhydrase II (hCA-II), human 11 beta-hydroxysteroid dehydrogenases type 1 (h11beta-HSD1), and human dual specificity phosphatase (hCDC25B) using in silico method. Methodology The 24 selected constituents of U. dioica (Stinging nettle) were studied on the docking behavior of hCA-II, h11beta-HSD1, and hCDC25B by using the Webina docking method. In addition to docking, toxicity analysis was also performed using the pkCSM free web server, respectively. Results Toxicity analysis has shown that six ligands (25%) of U. dioica (Stinging nettle) are predicted to have hERG II (Human ether-a-go-go-related gene) inhibition activity. The docking analysis showed that afzelin, stigmastane-3, 6-diol, and astragalin of U. dioica have shown the maximum binding energy (-7.2, -9.5, and -8.5 kcal/mol) with the hCA-II, h11beta-HSD1 and hCDC25B, respectively. Conclusions Thus, the current finding provides new knowledge about the 24 selected ligands of U. dioica (Stinging nettle) as potent inhibitory agents of human carbonic anhydrase II (hCA-II), human 11 beta-hydroxysteroid dehydrogenases type 1 (h11beta-HSD1) and human dual specificity phosphatase (hCDC25B).

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The combination of X-ray free-electron lasers (XFELs) with serial femtosecond crystallography represents cutting-edge technology in structural biology, allowing the study of enzyme reactions and dynamics in real time through the generation of `molecular movies'. This technology combines short and precise high-energy X-ray exposure to a stream of protein microcrystals. Here, the XFEL structure of carbonic anhydrase II, a ubiquitous enzyme responsible for the interconversion of CO2 and bicarbonate, is reported, and is compared with previously reported NMR and synchrotron X-ray and neutron single-crystal structures.

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In order to obtain topical and non-irritating anti-glaucoma drugs, novel semicarbazide-containing sulfonamide derivatives were designed and synthetized by sugar tail method in this study. The hydrophilic monosaccharides were expected to form interaction with the hydrophilic site of hCA II meanwhile the linker semicarbazides are used to further enhance water solubility, and more importantly, regulate the pH values of the target compounds in aqueous solution. First, all target compounds were synthesized and evaluated for their CA inhibitory activities. The results showed our target compounds demonstrated comparable activity to the positive control drug acetazolamide. The best derivative 11d exhibits an IC50 value of 14 nM for hCA II and 2086-fold selectivity over CA I. Subsequently, physicochemical properties study showed that the target compounds displayed very good water solubility (up to 3 %) and neutral pH value in solutions. Meanwhile, the artificial membrane permeability assay was performed to verify that the target compound could also pass through the membrane structure despite their strong water solubility. In the glaucomatous rabbit eye model, the applied topically representative compounds showed strongly lowered intraocular pressure (IOP), as 1 % or 2 % water solutions. Subsequent drug-like evaluation showed our target compounds possessed low hemolysis effect and low cytotoxicity toward human corneal epithelial cell line. Also, it was not found that these target compounds had significant inhibition of hERG and CYP. In addition, these novel analogs also displayed good liver microsomal metabolic stability and plasma stability. Finally, docking studies provided the rational binding modes of representative compounds in complex with hCA II. Taken together, these results suggested that compound 11d may be a promising hCA II inhibitor deserving further development.

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The secondary sulfonamide derivatives containing benzothiazole scaffold (1-10) were synthesized to determine their inhibition properties on two physiologically essential human carbonic anhydrases isoforms (hCAs, EC, 4.2.1.1), hCA I, and hCA II. The inhibitory effects of the compounds on hCA I and hCA II isoenzymes were investigated by comparing their IC50 and Ki values. The Ki values of compounds (1-10) against hCA I and hCA II are in the range of 0.052 ± 0.022-0.971 ± 0.280 and 0.025 ± 0.010-0.682 ± 0.335, respectively. Some of these inhibited the enzyme more effectively than the standard drug, acetazolamide. In particular, compounds 5 and 4 were found to be most effective on hCA I and hCA II.

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Advanced glycation end products are the most important species of glycation pathway, and cause disorders such as oxidative stress and diabetes. Sulfonamide compounds, which are generally known as widespread inhibitors, are potential agents used in different drug products, which can readily enter biological matrices. In the present work, the structure and activity of human carbonic anhydrase II studied in the presence of glucose as well as four sulfonamide agents from different views. These included enzyme kinetics, free lysine content, fluorescence spectroscopy, circular dichroism, and ROS measurement. Our results indicated that upon glycation, the structure of HCA II collapses and 8 to 13 lysine residues will be more available based on ligand incubation. Secondary and tertiary structural changes were also observed in the presence and absence of sulfonamide agents using fluorescence and circular dichroism methods, respectively. These spectroscopic data also showed a remarkable increase in hydrophobicity and decrease in α-helix contents during glycation, especially after 35 days of incubation. ROS assay was studied in the presence of glucose and sulfonamide compounds, that demonstrated the role of sulfonamide compounds in ROS formation in the presence of glucose in a synergistic manner. Overall, our data indicated that sulfonamides act as a stimulant factor upon prolonged interaction with HCA II and may intensify the complications of some disorders, such as diabetes and other conformational diseases.

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Background: Bunch berry (Lantana camara) is primarily composed of flavonoids and vitamin C; therefore, it has been shown to possess various medical characteristics, including the ability to relieve fever, inflammation, and urinary tract infections. Objective: In this study, we intended to assess twenty chosen constituents of Bunch berry as potent inhibitory agents of human acetylcholinesterase (hAchE), carbonic anhydrase II (hCA-II) and carboxylesterase 1 (hCES-1) employing in silico techniques. Methods: The twenty chosen Bunch berry components were examined about docking behaviour of hAchE, hCA-II and hCES-I by using the Swissdock method. Apart from to docking, Molecular physico-chemical, drug-likeness, ADME (ingesting, dispersing, metabolising, and excreting), and toxicity assessments were also performed utilising the Molinspiration, Swiss ADME, pkCSM, and STITCH web sites, correspondingly. Results: Eight ligands (40 %) have exhibited strict adherence to Lipinski's rule of five (Ro5), according to molecular physico-chemical study. Drug-likeness property analysis has shown that five ligands (25 %) of Bunch berry predicted to exhibit moderate bioactivity score against all the descriptors. ADME analysis has shown that five ligands (25 %) of Bunch berry are predicted to possess high gastrointestinal absorption property Toxicity analysis has shown that six ligands (30 %) of Bunch berry are predicted to have hERG II (Human ether-a-go-go-related gene) inhibition activity. According to the docking analysis, lantic acid has the lowest atomic binding energy for all three target enzymes, hAchE (-6.23 kcal/mol), hCA-II (-4.46 kcal/mol), and hCES-I (-5.99 kcal/mol), respectively. Conclusions: Thus the current find provides an advanced understanding the twenty selected ligands of Bunch berry as potent inhibitory agents of human acetylcholinesterase (hAchE), carbonic anhydrase II (hCA-II) and carboxylesterase 1 (hCES-1).

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We performed a study to present a phenotypic and genotypic characterization of a patient clinically diagnosed with carbonic anhydrase II (CAII) deficiency syndrome. Medical records were reviewed, and oral examination was performed. Sanger sequencing was undertaken for molecular diagnosis. The patient presented with osteopetrosis, renal tubular acidosis, cerebral calcification, blindness, deafness, and development delay. The oral manifestations included anterior open bite, posterior crossbite, tooth eruption impairment, and hypoplastic amelogenesis imperfecta (AI). Molecular analysis revealed a CA2 homozygous deletion (c.753delG, p.Asn252Thrfs*14) and confirmed the clinical diagnosis. This study suggests that AI can be another feature of CAII deficiency syndrome. For the first time, a CA2 disease-causing variant is reported to be associated with syndromic AI.

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Osteopetrosis is a rare inherited disease caused by osteoclast failure, resulting in increasing bone density in humans. Patients with osteopetrosis possess several dental and cranial complications. Since carbonic anhydrase II (CA-II) deficiency is a major cause of osteopetrosis, CA-II activators might be an attractive potential treatment option for osteopetrosis patients. We conducted comprehensive label-free quantitative proteomics analysis on Fluconazole-treated Dental Pulp Mesenchymal Stem/Stromal Cells from CA-II-Deficient Osteopetrosis Patients. We identified 251 distinct differentially expressed proteins between healthy subjects, as well as untreated and azole-treated derived cells from osteopetrosis patients. Twenty-six (26) of these proteins were closely associated with osteogenesis and osteopetrosis disease. Among them are ATP1A2, CPOX, Ap2 alpha, RAP1B and some members of the RAB protein family. Others include AnnexinA1, 5, PYGL, OSTF1 and PGAM4, all interacting with OSTM1 in the catalytic reactions of HCO3 and the Cl- channel via CAII regulation. In addition, the pro-inflammatory/osteoclast regulatory proteins RACK1, MTSE, STING1, S100A13, ECE1 and TRIM10 are involved. We have identified proteins involved in osteogenic and immune metabolic pathways, including ERK 1/2, phosphatase and ATPase, which opens the door for some CA activators to be used as an alternative drug therapy for osteopetrosis patients. These findings propose that fluconazole might be a potential treatment agent for CAII- deficient OP patients. Altogether, our findings provide a basis for further work to elucidate the clinical utility of azole, a CA activator, as a therapeutic for OP.

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Myocardial infarction (MI) is a significant threat to human health and life. Xue-Fu-Zhu-Yu Decoction (XFZYD), a renowned traditional Chinese medicine prescription for treating myocardial infarction, is known to play a significant role in the management of MI. However, its mechanism of action remains unclear. Through network pharmacology analysis of compound-target interactions, we have identified Carbonic Anhydrase II (CA2) as a critical target for XFZYD in the treatment of MI. Subsequently, we will embark on a target-based drug design approach with a focus on CA2 as the key target: Pharmacophore modeling: Two pharmacophore models were developed and validated to screen for small molecules with CA2 inhibitory features. Virtual screening: Based on two pharmacophore models, small molecules with the property of binding to the CA2 target were screened from a virtual screening library. Molecular docking: Molecular docking was employed to identify small molecules with stable binding affinity to CA2. ADMET prediction: ADMET models were utilized to screen for small molecules with favorable pharmacological properties. Molecular dynamics: Molecular dynamics simulations were further conducted to analyze the binding modes of the selected small molecules with CA2, ultimately resulting in the identification of Ligand 3 and Ligand 5 as small molecule inhibitors targeting CA2. Finally, the mechanisms underlying the anti-MI effects were discussed. The primary objective of this article is to uncover the mechanism by which XFZYD acts on MI and utilize it for drug development. These findings provide novel avenues for the development of anti-MI drugs.Communicated by Ramaswamy H. Sarma.

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Purpose: Vascular calcification is a hallmark of atherosclerosis (AS). We and others confirmed that carbonic anhydrase I (CA1) and CA2 increased expression and catalyzed calcium deposition in atherosclerotic aortas. Macrophages have been demonstrated to be strongly related to AS. This study aimed to clarify how and which macrophage subtypes regulate CA1 and CA2 expression to stimulate aortic calcification. Methods and Results: THP-1 cells were induced to form M0, M1 and M2 macrophage subtypes. These cells and their culture supernatants were separately incubated with human vascular smooth muscle cells (VSMCs). Calcification was strongly increased in VSMCs treated with ß-GP, a chemical inducer of cellular calcification, following incubation with M1 macrophages or their culture supernatants, and was much higher than that in VSMCs treated with ß-GP alone. Meanwhile, the expression of CA1 and CA2, as well as calcification marker genes, including Runx2, BMP-2 and ALP, was increased in VSMCs during this process. TNF-α levels were also increased in the culture medium of M1 macrophages. M0 and M2 macrophages or their supernatants did not significantly stimulate calcification in VSMCs. Following transfection with anti-CA1 or CA2 siRNAs, ß-GP-induced VSMCs showed decreased calcification, but the calcification level was partially increased when those VSMCs were incubated with the supernatants of M1 macrophages, while CA1 and CA2 expression as well as TNF-α levels were also elevated. When VSMCs were treated with TNF-α without ß-GP induction, calcification and the expression of CA1 and CA2 were also significantly increased. Conclusion: The results of this study suggest that M1 macrophages can increase CA1 and CA2 expression to promote atherosclerotic calcification in VSMCs by secreting TNF-α.

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A novel carbonic anhydrase II (CA II) from erythrocytes of camel (Camelus dromedarius) was purified to homogeneity using affinity chromatography and biochemically characterized. Specific activity of 140.88 U/mg was obtained with 745.17-fold purification and 25.37% yield. The enzyme was a monomer with a lower molecular weight (25 kDa) and lower Zn content (0.50 mol of Zn per mol of protein). The enzyme showed higher optimum temperature (70 °C) and pH (pH 9.0), moreover, it was stable at higher temperatures and strongly alkaline pH as judged by thermodynamic parameters (Ea, kd, Ed, t1/2, D-value, Z-value, ΔH, ΔG and ΔS). The enzyme was inhibited by cations (Al3+, Ca2+, Cd2+, Co2+, Cr3+, Cu2+, Fe3+, Ni2+, Mg2+ and Zn2+) as well as by anions (Br‾, CH3COO‾, ClO4‾, CN‾, F‾, HCO3‾, I‾, N3‾, NO3‾ and SCN‾), some anions (C6H5O73-, CO32-, SeO3‾ and SO42-) does not affect enzyme activity. Effect of various chemicals on enzyme activity was also investigated. Km, Vmax, kcat and kcat/Km values for 4-NPA were found to be 1.74 mM, 0.0093 U/mL, 0,0039 s-1 and 0,0023 s-1 mM-1, respectively. With these interesting biochemical properties, camel CA II represents promising candidate for harsh industrial applications, in particular, for a successful biomimetic CO2 sequestration process.

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Carbonic anhydrases (CAs) are a metalloenzyme family that have important roles in cellular processes including pH homeostasis and have been implicated in multiple pathological conditions. Small molecule inhibitors have been developed to target carbonic anhydrases, but the effects of post-translational modifications (PTMs) on the activity and inhibition profiles of these enzymes remain unclear. Here, we investigate the effects of phosphorylation, the most prevalent carbonic anhydrase PTM, on the activities and drug-binding affinities of human CAI and CAII, two heavily modified active isozymes. Using serine to glutamic acid (S > E) mutations to mimic the effect of phosphorylation, we demonstrate that phosphomimics at a single site can significantly increase or decrease the catalytic efficiencies of CAs, depending on both the position of the modification and the CA isoform. We also show that the S > E mutation at Ser50 of hCAII decreases the binding affinities of hCAII with well-characterized sulphonamide inhibitors including by over 800-fold for acetazolamide. Our findings suggest that CA phosphorylation may serve as a regulatory mechanism for enzymatic activity, and affect the binding affinity and specificity of small, drug and drug-like molecules. This work should motivate future studies examining the PTM-modification forms of CAs and their distributions, which should provide insights into CA physiopathological functions and facilitate the development of 'modform-specific' carbonic anhydrase inhibitors.

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Many proteins naturally carry metal centers, with a large share of them being in the active sites of several enzymes. Paramagnetic effects are a powerful source of structural information and, therefore, if the native metal is paramagnetic, or it can be functionally substituted with a paramagnetic one, paramagnetic effects can be used to study the metal sites, as well as the overall structure of the protein. One notable example is cobalt(II) substitution for zinc(II) in carbonic anhydrase. In this manuscript we investigate the effects of sodium thiocyanate on the chemical environment of the metal ion of the human carbonic anhydrase II. The electron paramagnetic resonance (EPR) titration of the cobalt(II) protein with thiocyanate shows that the EPR spectrum changes from A-type to C-type on passing from 1:1 to 1:1000-fold ligand excess. This indicates the occurrence of a change in the electronic structure, which may reflect a sizable change in the metal coordination environment in turn caused by a modification of the frozen solvent glass. However, paramagnetic nuclear magnetic resonance (NMR) data indicate that the metal coordination cage remains unperturbed even in 1:1000-fold ligand excess. This result proves that the C-type EPR spectrum observed at large ligand concentration should be ascribed to the low temperature at which EPR measurements are performed, which impacts on the structure of the protein when it is destabilized by a high concentration of a chaotropic agent.

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Osteopetrosis is a rare hereditary illness generated by failure in osteoclasts resulting in elevated bone densities. Patients with osteopetrosis possess several complications, like dental caries, earlier teeth loss, delayed eruption, malformed crowns and roots, and lamina dura thickening. Since deficiency of carbonic anhydrase II is a major cause behind osteopetrosis, carbonic anhydrase II activators have a large number of applications in osteopetrosis treatment. There is a lack of a comprehensive review on osteopetrosis, pathogenesis of dental abnormalities, and the role of carbonic anhydrase II activators in osteopetrosis treatment. To address this research gap, the authros perfomed a comprehensive review on osteopetrosis and its types, pathogenesis of dental abnormalities, and the role of carbonic anhydrase II activators in osteopetrosis treatment. A brief introduction to the pathogenesis of dental abnormalities and regeneration is provided in this survey. A discussion of types of osteopetrosis depending on genetic inheritance, such as autosomal dominant, autosomal recessive, and X-linked inheritance osteopetrosis, is presented in this survey. The paper also focuses on the importance of carbonic anhydrase II activators as a potential drug therapy for dental osteopetrosis. In addition, a brief note on the role of azole and fluconazole in treating osteopetrosis is given. Finally, future directions involving gene therapy for dental osteopetrosis are described.

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Acetylated triterpenoids betulin, oleanolic acid, ursolic acid, and glycyrrhetinic acid were converted into their succinyl-spacered acetazolamide conjugates. These conjugates were screened for their inhibitory activity onto carbonic anhydrase II and their cytotoxicity employing several human tumor cell lines and non-malignant fibroblasts. As a result, the best inhibitors were derived from betulin and glycyrrhetinic acid while those derived from ursolic or oleanolic acid were significantly weaker inhibitors but also of diminished cytotoxicity. A betulin-derived conjugate held a Ki = 0.129 µM and an EC50 = 8.5 µM for human A375 melanoma cells.

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