scholarly journals An efficient strategy to enhance binding affinity and specificity of a known isozyme inhibitor

2016 ◽  
Vol 14 (28) ◽  
pp. 6833-6839 ◽  
Author(s):  
Joo-Eun Jee ◽  
Jaehong Lim ◽  
Yong Siang Ong ◽  
Jessica Oon ◽  
Liqian Gao ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Binding Affinity ◽  
High Throughput ◽  
High Throughput Screening ◽  
Peptide Libraries ◽  
Binding Profile ◽  
Efficient Strategy

The binding profile of a known inhibitor, benzenesulfonamide, against a family of carbonic anhydrase isozymes was efficiently enhanced via high-throughput screening of customized combinatorial one-bead-one-compound peptide libraries.

Inhibition Profiling of Urease and Carbonic Anhydrase II by High- Throughput Screening and Molecular Docking Studies of Structurally Diverse Organic Compounds

2020 ◽  
Vol 17 ◽  
Author(s):  
Majid Ali ◽  
Syed Majid Bukhari ◽  
Asma Zaidi ◽  
Farhan A. Khan ◽  
Umer Rashid ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Carbonic Anhydrase ◽  
Metal Complexes ◽  
Organic Compounds ◽  
High Throughput ◽  
High Throughput Screening ◽  
Docking Studies ◽  
Carbonic Anhydrase Ii ◽  
Molecular Docking Studies ◽  
Ic50 Values

Background:: Structurally diverse organic compounds and available drugs were screened against urease and carbonic anhydrase II in a formulation acceptable for high-throughput screening. Objective: The study was conducted to find out potential inhibitors of urease and carbonic anhydrase II. Methods:: Quantification of the possible HITs was carried out by determining their IC50 values. Results and Discussion:: of several screened compounds including derivatives of oxadiazole, coumarins, chromane-2, 4- diones and metal complexes of cysteine-omeprazole showed promising inhibitory activities with IC50 ranging from 47 μM to 412 μM against the urease. The interactions of active compounds with active sites of enzymes were investigated through molecular docking studies which revealed that (R)-1-(4-amino-4-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl) butyl) guanidine possessing IC50 of 47 μM, interacts with one of the nickel metal atom of urease besides further interactions as predictable hydrogen bonds with KCX490, Asp633, His492, His407 and His409 along with Ala440 and 636. Bi-ligand metal complexes of 4-aminoantipyrine based Schiff bases showed activation of urease with AC50 ranging from 68 μM to 112 μM. Almost 21 compounds with varying functional groups including pyrimidines, oxadiazoles, imidazoles, hydrazides and tin based compounds were active carbonic anhydrase II inhibitors presenting 98 μM to 390 μM IC50 values. Several N-substituted sulfonamide derivatives were inactive against carbonic anhydrase II. Conclusion:: Among all the screened compounds, highly active inhibitor of carbonic anhydrase II was (4-(3- hydroxyphenyl)-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl) methanone with IC50 of 98.0 μM. This particular compound showed metallic interaction with Zn ion of carbonic anhydrase II through hydroxyl group of phenyl ring.

scholarly journals Process Automation toward Ultra-High-Throughput Screening of Combinatorial One-Bead-One-Compound (OBOC) Peptide Libraries

2012 ◽  
Vol 17 (3) ◽  
pp. 186-200 ◽  
Author(s):  
Junhoe Cha ◽  
Jaehong Lim ◽  
Yiran Zheng ◽  
Sylvia Tan ◽  
Yi Li Ang ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Peptide Libraries ◽  
Process Automation

scholarly journals Inhibition Profiling of Human Carbonic Anhydrase II by High-Throughput Screening of Structurally Diverse, Biologically Active Compounds

2006 ◽  
Vol 11 (7) ◽  
pp. 782-791 ◽  
Author(s):  
Rema Iyer ◽  
Albert A. Barrese ◽  
Shilpa Parakh ◽  
Christian N. Parker ◽  
Brian C. Tripp
Keyword(s):  
Carbonic Anhydrase ◽  
Small Molecules ◽  
Tannic Acid ◽  
High Throughput ◽  
Mechanism Of Action ◽  
High Throughput Screening ◽  
Biologically Active ◽  
Carbonic Anhydrase Ii ◽  
Hit Rate ◽  
Human Carbonic Anhydrase

Human carbonic anhydrase II (CA II), a zinc metalloenzyme, was screened against 960 structurally diverse, biologically active small molecules. The assay monitored CA II esterase activity against the substrate 4-nitrophenyl acetate in a format allowing high-throughput screening. The assay proved to be robust and reproducible with a hit rate of ∼2%. Potential hits were further characterized by determining their IC50 and Kd values and tested for nonspecific, promiscuous inhibition. Three known sulfonamide CA inhibitors were identified: acetazolamide, methazolamide, and celecoxib. Other hits were also found, including diuretics and antibiotics not previously identified as CA inhibitors, for example, furosemide and halazone. These results confirm that many sulfonamide drugs have CA inhibitory properties but also that not all sulfonamides are CA inhibitors. Thus many, but not all, sulfonamide drugs appear to interact with CA II and may target other CA isozymes. The screen also yielded several novel classes of nonsulfonamide inhibitors, including merbromin, thioxolone, and tannic acid. Although these compounds may function by some nonspecific mechanism (merbromin and tannic acid), at least 1 (thioxolone) appears to represent a genuine CA inhibitor. Thus, this study yielded a number of potentially new classes of CA inhibitors and preliminary experiments to characterize their mechanism of action.

scholarly journals Estimating Protein−Ligand Binding Affinity Using High-Throughput Screening by NMR

2008 ◽  
Vol 10 (6) ◽  
pp. 948-958 ◽  
Author(s):  
Matthew D. Shortridge ◽  
David S. Hage ◽  
Gerard S. Harbison ◽  
Robert Powers
Keyword(s):  
Ligand Binding ◽  
Binding Affinity ◽  
High Throughput ◽  
High Throughput Screening

High-Throughput Screening Assays for Estrogen Receptor by Using Coumestrol, a Natural Fluorescence Compound

2013 ◽  
Vol 19 (2) ◽  
pp. 253-258 ◽  
Author(s):  
Caihua Wang ◽  
Changhao Li ◽  
Haibing Zhou ◽  
Jian Huang
Keyword(s):  
Estrogen Receptor ◽  
Binding Affinity ◽  
High Throughput ◽  
High Throughput Screening ◽  
Binding Assay ◽  
Convex Curve ◽  
Nonspecific Adsorption ◽  
Plot Analysis ◽  
Detection And Identification ◽  
Reported Data

Estrogen receptor (ER) is a ligand-inducible transcriptional factor involving in cell growth, differentiation, and diseases, so detection and identification of compounds having estrogenic effects are of great importance in the drug discovery industry. We have developed and validated a rapid, simple, and homogeneous method that can detect estrogenic compounds. This human ERα/β binding assay uses fluorescence polarization (FP) by applying an autofluorescent phytoestrogen, coumestrol (CS). A nonspecific adsorption assay shows that no obvious nonspecific adsorption is detected between CS and ERs. In the Scatchard plot analysis, the convex curve exhibits a positive cooperative binding, indicating that the binding of CS induces a conformational change of the ER to form a dimer and increases the affinity for the additional CS. In the Hill plot analysis, CS shows moderate binding affinity with both ERα and ERβ, and the measured Kd of CS is 32.66 µM and 36.14 µM, respectively, indicating that CS is applicable to the ER binding assay for determination of potent ligands of moderate binding affinity. Four typical ligands are selected to verify the ER binding assays, and the results are consistent with the reported data. All of above make the FP method based on CS suitable for high-throughput screening.

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