Interaction of amide inhibitors with the active site of carbonic anhydrase: metal-induced deprotonation of the bound amide group is indicated by slow binding kinetics, by visible spectra of complexes with cobalt enzyme, and by pH effects on binding affinity

Biochemistry ◽  
1987 ◽  
Vol 26 (18) ◽  
pp. 5672-5679 ◽  
Author(s):  
Janice I. Rogers ◽  
Jogeshwar Mukherjee ◽  
Raja G. Khalifah
Keyword(s):  
Carbonic Anhydrase ◽  
Binding Affinity ◽  
Active Site ◽  
Amide Group ◽  
Binding Kinetics ◽  
Ph Effects ◽  
Visible Spectra

Computational Studies on Isolated Compounds of Sclerochloa dura; their Efficacy towards Carbonic Anhydrase Inhibition and Anti-cancer Drug Targets

2021 ◽  
Vol 18 ◽  
Author(s):  
Majid Ali ◽  
Asma Zaidi ◽  
Umar Farooq ◽  
Rizwana Sarwar ◽  
Syed Majid Bukhari
Keyword(s):  
Carbonic Anhydrase ◽  
Binding Affinity ◽  
Anticancer Drug ◽  
Active Site ◽  
Drug Targets ◽  
Docking Studies ◽  
Cancer Drug ◽  
Hydroxyl Groups ◽  
Carbonic Anhydrases

Background: In the previous study, we reported the isolation of six compounds from Sclerochloa dura and their in-vitro anti-inflammatory potential by their ability to inhibit phospholipase A2 (PLA2). The objective of the current study is to inspect the effect of these compounds on other expected targets. Methods: For this purpose, various targets and percentage activities are predicted through CoFFer (QSAR) web service. All six compounds under investigation represented 99-100% activity towards carbonic anhydrases (CAs) and 90-100% activity towards anticancer drug targets. As the active site of most of the carbonic anhydrase isozymes is conserved, we selected cytosolic human carbonic anhydrase II (hCA II) for docking studies which is ubiquitous and involved in various human disorders such as glaucoma, pulmonary edema, and epilepsy. Anticancer drug targets include vascular endothelial growth factor receptor 2 (VEGFR2), glucocorticoid receptor (GR), and tyrosine-protein kinase (c-SRC). Interaction of these compounds with hCA II (PDB ID: 3P4V) and anticancer drug targets such as VEGFR2 (ID: 3WZD), GR (ID: 5G5W), and c-SRC (ID: 2SRC) was analyzed through molecular docking studies using MOE (Molecular Operating Environment). Results: The findings suggested that most of these compounds represent excellent binding affinity with hCA II by interacting with zinc-coordinated water molecules through sulfonic acid and hydroxyl groups present in the blends. Similarly, five out of six compounds represented excellent interaction with VEGFR2. Interactions with GR indicated that compounds 2, 3, and 6 binds effectively compared to their co-crystallized ligands. However, among these, the excellent binding affinity with c-SRC was demonstrated by compounds 3 and 6. Conclusion: This study revealed that all these compounds exhibited excellent interaction with the active site of hCA II, however in the light of previously reported data and due to membrane barrier, only compound 1 (due to long hydrophobic tail) and compound 4 (due to absence of bulky carbohydrate groups), can only penetrate inside the cytosol. Compounds 2, 3, 4, and 6 containing bulky carbohydrate moieties cannot penetrate inside the cell, therefore, they might have selective nature towards membrane-bounded tumor-associated hCA IX. This anti-tumor property of compounds was also proved by docking studies with VEGFR2, GR, and c-SRC. Therefore, these compounds may have a synergistic effect against inflammation and cancer. The ADMET studies show that compounds have moderate absorption and permeability along with slight toxicity.

Active-site engineering of carbonic anhydrase and its application to biosensors

2000 ◽  
pp. 221-240 ◽  
Author(s):  
Jennifer A. Hunt ◽  
Charles A. Lesburg ◽  
David W. Christianson ◽  
Richard B. Thompson ◽  
Carol A. Fierke
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site

Insulin receptors: binding kinetics and structure-function relationship of insulin

1984 ◽  
Vol 64 (4) ◽  
pp. 1321-1378 ◽  
Author(s):  
S. Gammeltoft
Keyword(s):  
Plasma Membrane ◽  
Binding Affinity ◽  
Insulin Action ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Insulin Receptors ◽  
Binding Kinetics ◽  
Antigenic Determinants ◽  
Insulin Degradation ◽  
Recent Advances

During the last decade, earlier suggestions that insulin acts at the plasma membrane level via combination with receptors have been amply confirmed in studies of 125I-labeled insulin binding kinetics. Efforts have been devoted to the development of homogeneous, stable, and bioactive tracers, and a preparation of monoiodo[TyrA14]insulin showed 100-125% biological activity. The initially simple model of reversible, bimolecular, and noncooperative interaction between receptor and insulin has been revised to include the existence of at least three affinity states that may be linked to modulation of the biological response induced by the insulin-receptor complex. Thus negative cooperativity seems important in reducing oscillations of insulin action with variations in plasma insulin concentration, and formation of a high-affinity state or positive cooperativity may lead to desensitization of receptors. The kinetic phenomena suggest that receptor-binding affinity and function are actively regulated by insulin itself. At present the receptor model is purely functional and does not imply molecular mechanisms. However, recent advances in the analysis of receptor structure and biochemistry promise that the molecular equivalents of the kinetic phenomena may be elucidated in the near future. Furthermore the reaction between receptor and insulin is irreversible because of degradation of receptor-bound insulin, which may result in termination of the metabolic activation. Morphological and biochemical work suggests that internalization of the receptor-insulin complex from the plasma membrane transfers insulin to intracellular organelles like the lysosomes, the Golgi apparatus, or nucleus, where degradation by insulin protease takes place, whereas the receptor is recycled back to the membrane. Recent advances in the studies of biosynthesis and cellular dynamics of receptors indicate that intracellular processing and redistribution of binding sites may play a role in the mechanism of insulin action. Insulin receptors are widely distributed in all cell types, but evidence has accumulated that receptors show tissue and species variations in their functional properties regarding binding affinity, insulin specificity, cooperativity, and insulin degradation and in structural properties such as antigenic determinants and glycosidic composition. Perhaps these differences reflect cellular adaptations and variations in the physiological role of insulin.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Synthesis, Molecular Docking Analysis, and Carbonic Anhydrase Inhibitory Evaluations of Benzenesulfonamide Derivatives Containing Thiazolidinone

Molecules ◽  
2019 ◽  
Vol 24 (13) ◽  
pp. 2418
Author(s):  
Zuo-Peng Zhang ◽  
Ze-Fa Yin ◽  
Jia-Yue Li ◽  
Zhi-Peng Wang ◽  
Qian-Jie Wu ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site ◽  
Docking Studies ◽  
Active Site Residues ◽  
Single Crystal Diffraction ◽  
Docking Analysis ◽  
X Ray ◽  
Active Site Cavity ◽  
Molecular Docking Analysis ◽  
Positive Controls

To find novel human carbonic anhydrase (hCA) inhibitors, we synthesized thirteen compounds by combining thiazolidinone with benzenesulfonamide. The result of the X-ray single-crystal diffraction experiment confirmed the configuration of this class of compounds. The enzyme inhibition assays against hCA II and IX showed desirable potency profiles, as effective as the positive controls. The docking studies revealed that compounds (2) and (7) efficiently bound in the active site cavity of hCA IX by forming sufficient interactions with active site residues. The fragment of thiazolidinone played an important role in the binding of the molecules to the active site.

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