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Carbonic anhydrase IX (CAIX) is a promising target in cancer therapy especially in the case of hypoxia-induced tumors. The selective inhibition of CA isozymes is a challenging task in drug design and discovery process. Here, we performed fluorescence-binding studies and inhibition assay combined with molecular docking and molecular dynamics (MD) simulation analyses to determine the binding affinity of two synthesized triazolo-pyrimidine urea derived (TPUI and TPUII) compounds with CAIX and CAII. Fluorescence binding results are showing that molecule TPUI has an excellent binding-affinity for CAIX (kD = 0.048 μM). The TPUII also exhibits an appreciable binding affinity (kD = 7.52 μM) for CAIX. TPUI selectively inhibits CAIX as compared to TPUII in the 4-NPA assay. Docking studies show that TPUI is spatially well-fitted in the active site cavity of CAIX, and is involve in H-bond interactions with His94, His96, His119, Thr199 and Thr200. MD simulation studies revealed that TPUI efficiently binds to CAIX and essential active site residual interaction is consistent during the entire simulation of 40 ns. These studies suggest that TPUI appeared as novel class of CAIX inhibitor, and may be used as a lead molecule for the development of potent and selective CAIX inhibitor for the hypoxia-induced cancer therapy. 相似文献
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Immobilization of carbonic anhydrase by embedding and covalent coupling into nanocomposite hydrogel containing hydrotalcite 总被引:2,自引:0,他引:2
Poly(acrylic acid-co-acrylamide)/hydrotalcite (PAA-AAm/HT) nanocomposite hydrogels activated by N-hydroxysuccinimide (NHS) in the presence of N, N'-dicyclohexylcarbodiimide (DCC) were used to immobilize carbonic anhydrase (CA) by embedding and covalent coupling. Cryo Scanning Electron Microscope (CryoSEM) proved the presence of free water in the porous network structures of the swollen hydrogels. Fluorescence microscopy indicated the existence of the immobilized enzyme in the hydrogels. Compared with un-activated hydrogels, activated hydrogels could improve the amount of the immobilization of enzyme, and maximum enzyme loading is about 4.6 mg/g of support for the activated hydrogels. The porous embedding and multi-point covalent linkage between enzyme and hydrogels strengthened the secondary structure stability of enzyme and thus enhanced enzyme stability in the presence of organic solvent and at high temperature. The immobilized enzyme in the activated hydrogel with enhanced structural stability offers great potential as a method to stabilize enzyme for various applications. 相似文献
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Longlong Wang Jianjun Liang Yu Zhou Tao Tian Baoli Zhang Deqiang Duanmu 《International journal of molecular sciences》2021,22(15)
Carbonic anhydrase (CA) plays a vital role in photosynthetic tissues of higher plants, whereas its non-photosynthetic role in the symbiotic root nodule was rarely characterized. In this study, 13 CA genes were identified in the model legume Lotus japonicus by comparison with Arabidopsis CA genes. Using qPCR and promoter-reporter fusion methods, three previously identified nodule-enhanced CA genes (LjαCA2, LjαCA6, and LjβCA1) have been further characterized, which exhibit different spatiotemporal expression patterns during nodule development. LjαCA2 was expressed in the central infection zone of the mature nodule, including both infected and uninfected cells. LjαCA6 was restricted to the vascular bundle of the root and nodule. As for LjβCA1, it was expressed in most cell types of nodule primordia but only in peripheral cortical cells and uninfected cells of the mature nodule. Using CRISPR/Cas9 technology, the knockout of LjβCA1 or both LjαCA2 and its homolog, LjαCA1, did not result in abnormal symbiotic phenotype compared with the wild-type plants, suggesting that LjβCA1 or LjαCA1/2 are not essential for the nitrogen fixation under normal symbiotic conditions. Nevertheless, the nodule-enhanced expression patterns and the diverse distributions in different types of cells imply their potential functions during root nodule symbiosis, such as CO2 fixation, N assimilation, and pH regulation, which await further investigations. 相似文献
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Natural Polyphenols Selectively Inhibit β‐Carbonic Anhydrase from the Dandruff‐Producing Fungus Malassezia globosa: Activity and Modeling Studies
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Dr. Alessio Nocentini Dr. Silvia Bua Dr. Sonia Del Prete Dr. Yeganeh Entezari Heravi Prof. Ali A. Saboury Prof. Anastasia Karioti Prof. Anna Rita Bilia Dr. Clemente Capasso Prof. Paola Gratteri Prof. Claudiu T. Supuran 《ChemMedChem》2018,13(8):816-823
Around 50 % of the worldwide population is affected by dandruff, which is triggered by a variety of factors. The yeast Malassezia globosa has been labeled as the most probable causative agent for the onset of dandruff. The β‐carbonic anhydrase (CA) of MgCA was recently validated as an anti‐dandruff target, with its inhibition being responsible for in vivo growth defects in the fungus. As classical CA inhibitors of the sulfonamide type give rise to permeability problems through biological membranes, finding non‐sulfonamide alternatives for MgCA inhibition is of considerable interest in the cosmetic field. We recently screened a large library of human (h) CA inhibitors for MgCA inhibition, including different chemotypes, such as monothiocarbamates, dithiocarbamates, phenols, and benzoxaboroles. Herein, we expanded the research toward new MgCA inhibitors by considering a set of natural polyphenols (including flavones, flavonols, flavanones, flavanols, isoflavones, and depsides) that exhibited MgCA inhibitory activity in the micromolar range, as well as selectivity for the fungal isozyme over off‐target human isoforms. The binding mode of representative derivatives within the MgCA catalytic cleft was investigated by docking studies using a homology‐built model. 相似文献
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Structure–Activity Relationships of Benzenesulfonamide‐Based Inhibitors towards Carbonic Anhydrase Isoform Specificity
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Avni Bhatt Dr. Brian P. Mahon Vinicius Wilian D. Cruzeiro Dr. Benedetta Cornelio Dr. Marie Laronze‐Cochard Dr. Mariangela Ceruso Prof. Dr. Janos Sapi Dr. Graham A. Rance Prof. Dr. Andrei N. Khlobystov Assoc. Prof. Dr. Antonella Fontana Prof. Dr. Adrian Roitberg Prof. Dr. Claudiu T. Supuran Prof. Dr. Robert McKenna 《Chembiochem : a European journal of chemical biology》2017,18(2):213-222
Carbonic anhydrases (CAs) are implicated in a wide range of diseases, including the upregulation of isoforms CA IX and XII in many aggressive cancers. However, effective inhibition of disease‐implicated CAs should minimally affect the ubiquitously expressed isoforms, including CA I and II, to improve directed distribution of the inhibitors to the cancer‐associated isoforms and reduce side effects. Four benzenesulfonamide‐based inhibitors were synthesized by using the tail approach and displayed nanomolar affinities for several CA isoforms. The crystal structures of the inhibitors bound to a CA IX mimic and CA II are presented. Further in silico modeling was performed with the inhibitors docked into CA I and XII to identify residues that contributed to or hindered their binding interactions. These structural studies demonstrated that active‐site residues lining the hydrophobic pocket, especially positions 92 and 131, dictate the positional binding and affinity of inhibitors, whereas the tail groups modulate CA isoform specificity. Geometry optimizations were performed on each ligand in the crystal structures and showed that the energetic penalties of the inhibitor conformations were negligible compared to the gains from active‐site interactions. These studies further our understanding of obtaining isoform specificity when designing small molecule CA inhibitors. 相似文献