Interaction of the unique competitive inhibitor imidazole and related compounds with the active site metal of carbonic anhydrase: linkage between pH effects on the inhibitor binding affinity and pH effects on the visible spectra of inhibitor complexes with the cobalt-substituted enzyme

Biochemistry ◽  
1987 ◽  
Vol 26 (22) ◽  
pp. 7057-7063 ◽  
Author(s):  
Raja G. Khalifah ◽  
Janice I. Rogers ◽  
Jogeshwar Mukherjee
Keyword(s):  
Carbonic Anhydrase ◽  
Binding Affinity ◽  
Active Site ◽  
Competitive Inhibitor ◽  
Ph Effects ◽  
Inhibitor Binding ◽  
Visible Spectra ◽  
Related Compounds

Competitive inhibitor binding to the binuclear copper active site in tyrosinase

1981 ◽  
Vol 103 (23) ◽  
pp. 7001-7003 ◽  
Author(s):  
Marjorie E. Winkler ◽  
Konrad Lerch ◽  
Edward I. Solomon
Keyword(s):  
Active Site ◽  
Competitive Inhibitor ◽  
Binuclear Copper ◽  
Inhibitor Binding

scholarly journals Carbonic Anhydrase Activators. Part 191 Spectroscopic and Kinetic Investigations for the Interaction of Isozymes I and II With Primary Amines

1997 ◽  
Vol 4 (4) ◽  
pp. 221-227 ◽  
Author(s):  
Fabrizio Briganti ◽  
Andrea Scozzafava ◽  
Claudiu T. Supuran
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site ◽  
Metal Ion ◽  
Competitive Inhibitor ◽  
The Other ◽  
Primary Amines ◽  
Hydrophobic Pocket ◽  
X Ray ◽  
Active Site Cavity ◽  
Kinetic Investigations

The interactions of Zn(II)- and Co(II)-substituted carbonic anhydrase (CA) isozymes I and II with amine type activators such as histamine, serotonin, phenetylamine dopamine and benzylhydrazine have been investigated kinetically, and spectroscopically. All of such activators are of the non-competitive type towards CO2 hydration and 4-nitrophenylacetate hydrolysis for both human isozymes (HCA I and HCA II). The electronic spectra of the adducts of Co(II)CA with amine activators are similar to the spectrum of the previously reported Co(II)CAII-phenol adduct, the only known competitive inhibitor towards CO2 hydration, where the phenol molecule binds into the hydrophobic pocket of the active site. This is a direct spectroscopic evidence that the activator molecules bind within the active site, but not directly to the metal ion. Recent X-ray crystallographic data for the adduct of HCA II with histamine show that the activator molecule is bound at the entrance of the active site cavity, near to residues His 64, Asn 62 and Gln 92, where actively aids in shuttling protons between the active site and the environment. Similar arrangements probably occur for the other activators reported in the present paper.

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.

scholarly journals Cryo-EM reveals disrupted human p97 allosteric activation by disease mutations and inhibitor binding

2021 ◽  
Author(s):  
Brian Caffrey ◽  
Xing Zhu ◽  
Alison Berezuk ◽  
Katharine Tuttle ◽  
Sagar Chittori ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Active Site ◽  
Competitive Inhibitor ◽  
Vital Role ◽  
Allosteric Activation ◽  
Inhibitor Binding ◽  
Aaa Atpase ◽  
Disease Mutations ◽  
D2 Domain ◽  
Potential Cancer

The human AAA ATPase p97, a potential cancer target, plays a vital role in clearing misfolded proteins. p97 dysfunction is also known to play a crucial role in several neurodegenerative disorders. Here, we present cryo-EM structural analyses of four disease mutants p97R155H, p97R191Q, p97A232E, p97D592N, as well as p97E470D, implicated in resistance to the drug CB-5083. These structures demonstrate that the mutations affect nucleotide-driven p97 allosteric activation by predominantly interfering with either the coupling between the D1 and N-terminal domains (p97R155H and p97R191Q), the inter-protomer interactions (p97A232E), or the coupling between D1 and D2 nucleotide domains (p97D592N, p97E470D). We also show that binding of the competitive inhibitor CB-5083 to the D2 domain prevents conformational changes similar to that seen for mutations that affect coupling between D1 and D2 domains. Our studies enable tracing of the path of allosteric activation across p97 and establish a common mechanistic link between active site inhibition and defects in allosteric activation by disease-causing mutations.

scholarly journals Inhibition of Butyrylcholinesterase and Human Monoamine Oxidase-B by the Coumarin Glycyrol and Liquiritigenin Isolated from Glycyrrhiza uralensis

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3896
Author(s):  
Geum Seok Jeong ◽  
Myung-Gyun Kang ◽  
Joon Yeop Lee ◽  
Sang Ryong Lee ◽  
Daeui Park ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Binding Affinity ◽  
Competitive Inhibitor ◽  
Glycyrrhiza Uralensis ◽  
Form Hydrogen Bond ◽  
Docking Simulations ◽  
Mao B ◽  
Mao A ◽  
Ic50 Values ◽  
Noncompetitive Inhibitor

Eight compounds were isolated from the roots of Glycyrrhiza uralensis and tested for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities. The coumarin glycyrol (GC) effectively inhibited butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) with IC50 values of 7.22 and 14.77 µM, respectively, and also moderately inhibited MAO-B (29.48 µM). Six of the other seven compounds only weakly inhibited AChE and BChE, whereas liquiritin apioside moderately inhibited AChE (IC50 = 36.68 µM). Liquiritigenin (LG) potently inhibited MAO-B (IC50 = 0.098 µM) and MAO-A (IC50 = 0.27 µM), and liquiritin, a glycoside of LG, weakly inhibited MAO-B (>40 µM). GC was a reversible, noncompetitive inhibitor of BChE with a Ki value of 4.47 µM, and LG was a reversible competitive inhibitor of MAO-B with a Ki value of 0.024 µM. Docking simulations showed that the binding affinity of GC for BChE (−7.8 kcal/mol) was greater than its affinity for AChE (−7.1 kcal/mol), and suggested that GC interacted with BChE at Thr284 and Val288 by hydrogen bonds (distances: 2.42 and 1.92 Å, respectively) beyond the ligand binding site of BChE, but that GC did not form hydrogen bond with AChE. The binding affinity of LG for MAO-B (−8.8 kcal/mol) was greater than its affinity for MAO-A (−7.9 kcal/mol). These findings suggest GC and LG should be considered promising compounds for the treatment of Alzheimer’s disease with multi-targeting activities.

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