scholarly journals Structure Activity Relationships of Flavonoids as Potent α-Amylase Inhibitors

2014 ◽  
Vol 9 (8) ◽  
pp. 1934578X1400900 ◽  
Author(s):  
Erdong Yuan ◽  
Benguo Liu ◽  
Qingyi Wei ◽  
Jiguo Yang ◽  
Lei Chen ◽  
...  
Keyword(s):  
Fluorescence Quenching ◽  
Fluorescence Spectroscopy ◽  
Binding Site ◽  
Hydroxyl Group ◽  
Binding Affinities ◽  
Binding Force ◽  
Structure Activity ◽  
Competitive Inhibitors ◽  
Quenching Process ◽  
Amylase Inhibitors

The effects of three flavonoids (quercetin, luteolin, diosmetin) on α-amylase were examined by enzymatic kinetics and fluorescence spectroscopy. The three test flavonoids were non-competitive inhibitors of the enzyme. Addition of flavonoids led to fluorescence quenching of α-amylase. The quenching was initiated from the formation of a complex between the flavonoids and the enzyme, corresponding to a static quenching process. An α-amylase molecule provides a binding site for the test flavonoid. The main binding force was hydrophobic. The decreasing order of inhibition of α-amylase by flavonoids and the binding force was luteolin, diosmetin, and quercetin. It is demonstrated that hydroxylation in ring C and methylation of the hydroxyl group in ring B of flavonoids may weaken the binding affinities to α-amylase.

STEROID AND PHYTO-OESTROGEN BINDING TO SHEEP UTERINE RECEPTORS IN VITRO

1972 ◽  
Vol 52 (2) ◽  
pp. 299-310 ◽  
Author(s):  
D. A. SHUTT ◽  
R. I. COX
Keyword(s):  
Binding Sites ◽  
Biochanin A ◽  
Hydroxyl Group ◽  
Binding Affinities ◽  
Structure Activity ◽  
Biological Potency ◽  
Competitive Protein Binding ◽  
Relationship Of

SUMMARY The binding affinities and receptor specificity of sheep uterine cytosol for steroid oestrogens and also for weak plant oestrogens of the isoflavone and coumestan groups and some synthetic compounds were studied. The binding affinities of the weak oestrogens fall within a range which has usually been neglected. Relative molar binding (RMB) affinities for the steroid oestrogens confirmed the importance of the phenolic 3-hydroxyl group and the influence of substitutions at C-16 and C-17, as seen with uterine cytosols from other species. Relative molar binding affinities were very much lower when the oestrogens were present as sulphate esters, glucosiduronate and methyl ether derivatives; acetates showed similar RMB affinities to their parent compounds. Phyto-oestrogens were found to compete with oestradiol for binding sites. Coumestrol and miroestrol had the highest RMB affinities of about 5 (oestradiol-17β = 100) when incubated at 25 °C, and values for genistein, equol, daidzein and O-desmethylangolensin lay between 1 and 0·05. The mono-methoxy compounds, biochanin A, formononetin and 4′-methoxy-coumestrol had RMB affinities of less than 0·01. Incubation at 37, 25 and 4 °C showed that RMB affinities were greater at the lower temperatures. Relative molar binding affinities of the phyto-oestrogens in vitro compared with their oestrogenic potencies in vivo showed that the ranking of most of the compounds by these two criteria was similar. Structure-activity correlations were deduced from the results. A similar relationship of RMB affinity to biological potency was also noted for the steroid oestrogens and a homologous series of stilbenediols. The results obtained are relevant to competitive protein-binding analyses and to the mechanism of action of oestrogens and phyto-oestrogens.

STRUCTURE–ACTIVITY RELATIONSHIPS OF CORTICOSTEROID FEEDBACK AT THE HYPOTHALAMIC LEVEL

1977 ◽  
Vol 74 (3) ◽  
pp. 415-424 ◽  
Author(s):  
M. T. JONES ◽  
E. W. HILLHOUSE ◽  
J. L. BURDEN
Keyword(s):  
Binding Site ◽  
Delayed Feedback ◽  
Hydroxyl Group ◽  
Hydroxyl Groups ◽  
Rat Hypothalamus ◽  
Structure Activity Relationships ◽  
Corticotrophin Releasing Factor ◽  
Structure Activity ◽  
Hypothalamic Level

SUMMARY Structure–activity studies on the corticosteroid fast and delayed feedback receptor mechanisms controlling the secretion of corticotrophin releasing factor (CRF) were carried out with the rat hypothalamus in vitro. The secretion of CRF was induced by acetylcholine (3 pg/ml). The fast feedback receptor appears highly specific, and the structure essential for efficacy involves an 11β-hydroxyl group and an unblocked 21-hydroxyl group. Several steroids showed antagonism and so the binding site is not very specific. 18-Hydroxy,11-deoxycorticosterone, progesterone, 17α-hydroxyprogesterone and 11-deoxycorticosterone were antagonists of fast feedback. The delayed feedback receptor required either an 11β- or a 21-hydroxyl group for efficacy. The binding site required a 17-hydroxyl group when the 11β- or 21-hydroxyl groups were absent. Binding also involved the 3-oxo,4,5-ene structure since steroids in which these are absent were inactive.

Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra Terminal Domain

2020 ◽  
Author(s):  
Luke Adams ◽  
Lorna E. Wilkinson-White ◽  
Menachem J. Gunzburg ◽  
Stephen J. Headey ◽  
Martin J. Scanlon ◽  
...  
Keyword(s):  
Binding Site ◽  
Systematic Approach ◽  
Structural Information ◽  
Peptide Binding ◽  
Chemical Diversity ◽  
Chemical Probes ◽  
Protein Targets ◽  
Structure Activity ◽  
Peptide Binding Site ◽  
Selection Of

The development of low-affinity fragment hits into higher affinity leads is a major hurdle in fragment-based drug design. Here we demonstrate an approach for the Rapid Elaboration of Fragments into Leads (REFiL) applying an integrated workflow that provides a systematic approach to generate higher-affinity binders without the need for structural information. The workflow involves the selection of commercial analogues of fragment hits to generate preliminary structure-activity relationships. This is followed by parallel microscale chemistry using chemoinformatically designed reagent libraries to rapidly explore chemical diversity. Upon completion of a fragment screen against Bromodomain-3 extra terminal (BRD3-ET) domain we applied the REFiL workflow, which allowed us to develop a series of tetrahydrocarbazole ligands that bind to the peptide binding site of BRD3-ET. With REFiL we were able to rapidly improve binding affinity >30-fold. The REFiL workflow can be applied readily to a broad range of protein targets without the need of a structure, allowing the efficient evolution of low-affinity fragments into higher affinity leads and chemical probes.<br>

scholarly journals The Inhibitory Effects of Plant Derivate Polyphenols on the Main Protease of SARS Coronavirus 2 and Their Structure–Activity Relationship

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1924
Author(s):  
Thi Thanh Hanh Nguyen ◽  
Jong-Hyun Jung ◽  
Min-Kyu Kim ◽  
Sangyong Lim ◽  
Jae-Myoung Choi ◽  
...  
Keyword(s):  
Structure Activity Relationship ◽  
Garlic Extract ◽  
Activity Relationship ◽  
Hydroxyl Group ◽  
Inhibitory Effects ◽  
Structure Activity ◽  
Main Protease ◽  
Ic50 Values ◽  
Km Value ◽  
Novel Coronavirus

The main protease (Mpro) is a major protease having an important role in viral replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus that caused the pandemic of 2020. Here, active Mpro was obtained as a 34.5 kDa protein by overexpression in E. coli BL21 (DE3). The optimal pH and temperature of Mpro were 7.5 and 37 °C, respectively. Mpro displayed a Km value of 16 μM with Dabcyl-KTSAVLQ↓SGFRKME-Edans. Black garlic extract and 49 polyphenols were studied for their inhibitory effects on purified Mpro. The IC50 values were 137 μg/mL for black garlic extract and 9–197 μM for 15 polyphenols. The mixtures of tannic acid with puerarin, daidzein, and/or myricetin enhanced the inhibitory effects on Mpro. The structure–activity relationship of these polyphenols revealed that the hydroxyl group in C3′, C4′, C5′ in the B-ring, C3 in the C-ring, C7 in A-ring, the double bond between C2 and C3 in the C-ring, and glycosylation at C8 in the A-ring contributed to inhibitory effects of flavonoids on Mpro.

scholarly journals Antibacterial Activity of Fluorobenzoylthiosemicarbazides and Their Cyclic Analogues with 1,2,4-Triazole Scaffold

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 170
Author(s):  
Urszula Kosikowska ◽  
Monika Wujec ◽  
Nazar Trotsko ◽  
Wojciech Płonka ◽  
Piotr Paneth ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Resistant Bacteria ◽  
Binding Affinities ◽  
Substitution Pattern ◽  
Minimal Inhibitory Concentrations ◽  
Gram Positive Bacteria ◽  
Structure Activity ◽  
Drug Resistant Bacteria ◽  
Reference Strains

The development of drug-resistant bacteria is currently one of the major challenges in medicine. Therefore, the discovery of novel lead structures for the design of antibacterial drugs is urgently needed. In this structure–activity relationship study, a library of ortho-, meta-, and para-fluorobenzoylthiosemicarbazides, and their cyclic analogues with 1,2,4-triazole scaffold, was created and tested for antibacterial activity against Gram-positive bacteria strains. While all tested 1,2,4-triazoles were devoid of potent activity, the antibacterial response of the thiosemicarbazides was highly dependent on substitution pattern at the N4 aryl position. The optimum activity for these compounds was found for trifluoromethyl derivatives such as 15a, 15b, and 16b, which were active against both the reference strains panel, and pathogenic methicillin-sensitive and methicillin-resistant Staphylococcus aureus clinical isolates at minimal inhibitory concentrations (MICs) ranging from 7.82 to 31.25 μg/mL. Based on the binding affinities obtained from docking, the conclusion can be reached that fluorobenzoylthiosemicarbazides can be considered as potential allosteric d-alanyl-d-alanine ligase inhibitors.

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