• Title/Summary/Keyword: Competitive inhibitors

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3D-QSAR, Docking and Molecular Dynamics Simulation Study of C-Glycosylflavones as GSK-3β Inhibitors

  • Ghosh, Suparna;Keretsu, Seketoulie;Cho, Seung Joo
    • Journal of Integrative Natural Science
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    • v.13 no.4
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    • pp.170-180
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    • 2020
  • Abnormal regulation, hyperphosphorylation, and aggregation of the tau protein are the hallmark of several types of dementia, including Alzheimer's Disease. Increased activity of Glycogen Synthase Kinase-3β (GSK-3β) in the Central Nervous System (CNS), increased the tau hyperphosphorylation and caused the neurofibrillary tangles (NFTs) formation in the brain cells. Over the last two decades, numerous adenosine triphosphate (ATP) competitive inhibitors have been discovered that show inhibitory activity against GSK-3β. But these compounds exhibited off-target effects which motivated researchers to find new GSK-3β inhibitors. In the present study, we have collected the dataset of 31 C-Glycosylflavones derivatives that showed inhibitory activity against GSK-3β. Among the dataset, the most active compound was docked with the GSK-3β and molecular dynamics (MD) simulation was performed for 50 ns. Based on the 50 ns MD pose of the most active compound, the other dataset compounds were sketched, minimized, and aligned. The 3D-QSAR based Comparative Molecular Field Analysis (CoMFA) model was developed, which showed a reasonable value of q2=0.664 and r2=0.920. The contour maps generated based on the CoMFA model elaborated on the favorable substitutions at the R2 position. This study could assist in the future development of new GSK-3β inhibitors.

Tyrosinase Inhibitors Isolated from the Edible Brown Alga Ecklonia stolonifera

  • Kang, Hye-Sook;Kim, Hyung-Rak;Byun, Dae-Seok;Son, Byeng-Wha;Nam, Taek-Jeong;Choi , Jae-Sue
    • Archives of Pharmacal Research
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    • v.27 no.12
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    • pp.1226-1232
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    • 2004
  • Extracts from seventeen seaweeds were determined for tyrosinase inhibitory activity using mushroom tyrosinase with L-tyrosine as a substrate. Only one of them, Ecklonia stolonifera OKAMURA (Laminariaceae) belonging to brown algae, showed high tyrosinase inhibitory activity. Bioassay-guided fractionation of the active ethyl acetate (EtOAc) soluble fraction from the methanolic extract of E. stolonifera, led us to the isolation of phloroglucinol derivatives [phloroglucinol (1), eckstolonol (2), eckol (3), phlorofucofuroeckol A (4), and dieckol (5)]. Compounds 1~5 were found to inhibit the oxidation of L-tyrosine catalyzed by mushroom tyrosinase with $IC_{50}$ values of 92.8, 126, 33.2, 177, and 2.16 ${\mu}g$ /mL, respectively. It was compared with those of kojic acid and arbutin, well-known tyrosinase inhibitors, with $IC_{50}$ values of 6.32 and 112 ${\mu}g$ / mL, respectively. The inhibitory kinetics analyzed from Lineweaver-Burk plots, showed compounds 1 and 2 to be competitive inhibitors with $K_i$ of $2.3{\times}10^{-4}\;and\;3.1{times}10^{-4}$ M, and compounds 3~5 to be noncompetitive inhibitors with $K_i$ of $1.9{\times}10^{-5},\;1.4{\times}10^{-3}\;and\;1.5{\times}10^{-5}$ M, respectively. This work showed that phloroglucinol derivatives, natural compounds found in brown algae, could be involved in the control of pigmentation in plants and other organisms through inhibition of tyrosinase activity using L-tyrosine as a substrate.

Inactivation Study of Pyridine-Linked Dehydrogenases by $N^1$-Alkylnicotinamide Chlorides ($N^1$-Alkylnicotinamide Chloride 유도체에 의한 탈수소 효소의 불활성화에 관한 연구)

  • Kim Soo-Ja;Lee Hyun Jae
    • Journal of the Korean Chemical Society
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    • v.20 no.5
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    • pp.406-416
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    • 1976
  • A series of $N^1$-alkylnicotinamide chlorides, $N^1$-methyl-to $N^1$-dodecylnicotinamides inclusive were studied with rabbit muscle L-${\alpha}$-glycerophosphate dehydrogenase to investigate the possibility of reversible and irreversible inactivation of the pyridine-linked dehydrogenases by the coenzyme-competitive inhibitor derivatives. The inhibition of the enzyme by $N^1$-alkylnicotinamide chlorides was demonstrated to be reversible at the dilute concentration of the inhibitors but this reversible inhibition was found to be followed by an irreversible time-dependent inactivation measuable at high concentrations of the inhibitors. The properties of this time-dependent inactivation were discussed on the basis of the denaturation of the enzyme by the binding of small micelle-like structures formed at higher concentrations of the inhibitors.

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Development of a FRET-based High-Throughput Screening System for the Discovery of Hsp90 Inhibitors

  • Oh, Sang-Mi;Ko, Yeon-Jin;Lee, Han-Jae;Kim, Jong-Hoon;Chung, Young-Sun;Park, Seung-Bum
    • Bulletin of the Korean Chemical Society
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    • v.32 no.9
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    • pp.3229-3232
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    • 2011
  • A FRET-based high-throughput screening system was developed for the discovery of competitive smallmolecule Hsp90 inhibitors. The biarsenical fluorescein derivative FlAsH and dabcyl-conjugated Hsp90 inhibitor GM were employed as the FRET donor and quencher, respectively. The spatial proximity perturbation between FlAsH-labeled Hsp90N and GM-dabcyl upon treatment of a small molecule led to changes in the FRET-induced fluorescence, monitored in a high-throughput fashion.

Prolyl Endopeptidase Inhibitors from Caryophylli Flos

  • Lee, Kyung-Hee;Kwak, Jong-Hwan;Lee, Kyung-Bok;Song, Kyung-Sik
    • Archives of Pharmacal Research
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    • v.21 no.2
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    • pp.207-211
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    • 1998
  • Three prolyl endopeptidase inhibitors were isolated and identified as luteolin, quercetin and ${\beta}$-sitosterol-3-O-${\beta}$-D-glucopyranoside with $IC_{50}$ of 0.17, 0.19 and 27.5 ppm, respectively. The inhibition of two flavonoids were non-competitive with substrate. Twenty authentic flavonoids were tested in order to investigate structure-activity relationship. No significant relationship was found in them, however, catechol moiety of B-ring and 7-OH group in flavonoid skeleton were seemed to be responsible for the stronger activity.

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Studies on Screening and Isolation of .$\alpha$-Amylase Inhibitors of Soil Microorganisms (I)

  • Kwak, Jin-Hwan;Choi, Eung-Chil;Kim, Byong-Kak
    • Archives of Pharmacal Research
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    • v.8 no.2
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    • pp.67-75
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    • 1985
  • To find emylase inhibitors produced by microorganisms from soil, a strain which had a strong inhibitory activity against bacteria .alpha.-amylase was isolated from the soil smaple collected in Seoul. The morphological and physiological characteristics of this strain on several media and its utilization of carbon sources showed that it was one of Streptomyces specties according to the international Streptomyces Project method. The amylase inhibitor of this strain was purified by means of acetone precipitation, adsorption on Amberlite XAD-2, and column chromatography on Amberlite CG-50 and SP-Sephadex C-25. The inhibitor was stable at the pH range of 1-10 and at 100.deg.C for half an hour, and had inhibitory activities against other amylases such as salivary .alpha.-amylase, pancreatic .alpha.-amylase, fungal .alpha.-amylase and glucoamylase. The kinetic studies of the inhibitor showed that its inhibitory effect on starch hydrolysis by .alpha.-amylase was non-competitive.

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Total synthesis of deoxy-azasugars

  • Pyun, Sung-Jae;Oh, Chang-Young;Lee, Kee-Young;Kim, Yong-Hyun;Lee, Yiu-Suk;Pharm, Van-Thoai;Ham, Won-Hun
    • Proceedings of the PSK Conference
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    • 2002.10a
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    • pp.233.1-233.1
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    • 2002
  • Azasugars, which have been called the "sugar-shaped" alkaloids from plants. are reversible. competitive inhibitors of glycosidases. The purpose of these natural products is possibly to inhibit the carbohydrate metabolism and consequently the growth of plant consuming pests. Since selective glycosidase inhibitors have a large number of interesting potential applications including treatment of AIDS, diabetes. and tumor metastasis. they have received a considerable attentions. (omitted)

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Characterization of Thiol Protease Inhibitor Isolated from Streptornyces sp. KISl3 (Streptomyces sp. KIS13 균주에서 분리한 thiol계 단백질분해효소 저해물질의 특성)

  • 김인섭;이계준
    • Microbiology and Biotechnology Letters
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    • v.18 no.5
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    • pp.501-505
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    • 1990
  • Streptomyces sp. KISl3 isolated from soil was found to produce low molecular weight thiol protease inhibitors. The protease inhibitor production was closely linked to the cell growth and regulated by growth condition. The inhibitor was purified from the culture broth through butanol extraction, silicagel 60 column chromatography, Sephadex LH-20 gel filtration and preparative HPLC. The inhibitor showed specific inhibitory activity to thiol protease such as papain, picin and bromelain. The mode of inhibition against papain to Hammersten casein as a substrate was non-competitive.

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Inhibitory Effects of Steppogenin and Oxyresveratrol from Morus alba L. against Yeast ${\alpha}$-Glucosidase (뽕나무에서 분리한 Steppogenin과 Oxyresveratrol의 효모 ${\alpha}$-Glucosidase의 억제효과)

  • Chin, Hwi-Seung;NamKung, Woo
    • YAKHAK HOEJI
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    • v.54 no.5
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    • pp.398-402
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    • 2010
  • [ ${\alpha}$ ]Glucosidase inhibitor is a target in the treatment of type II diabetes through the mainly inhibition of glucose levels after meals. In this study, we purified steppogenin and oxyresveratrol from the stem of Morus alba L. and examined their inhibitory activity against yeast ${\alpha}$-glucosidase. Steppogenin and oxyresveratrol were inhibited yeast ${\alpha}$-glucosidase in a dose dependent manner. The $IC_{50}$ activities (50% inhibition) were 34.4 and 9.3 ${\mu}M$, respectively. The kinetic inhibition of steppogenin showed noncompetitive inhibition ($K_m:1.1{\times}10^{-3}M$; $K_i:1{\times}10^{-5}M$), meanwhile oxyresveratrol showed competitive inhibition ($K_m:4.3{\times}10^{-3}M$; $K_i:3.4{\times}10^{-6}M$) against yeast ${\alpha}$-glucosidase. These results indicate that steppogenin and oxyresveratrol are noncompetitive and competitive inhibitors, respectively, against yeast ${\alpha}$-glucosidase.

Synthesis of 1,2,3-and 1,2,4-Triazole Isonucleosides as Potential antiviral agents

  • Jeong, Soon-Yong;Kim, Myong-Jung;Chun, Moon-Won
    • Proceedings of the PSK Conference
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    • 2003.10b
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    • pp.181.2-181.2
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    • 2003
  • Inosine monophosphate dehydrogenase(IMPDH) catalyzes the $NAD^+$-dependent oxidation of IMP to XMP, the rate limiting step in the de novo biosynthesis of guanine nucleotide. Its critical role at the metabolic branch point in purine nucleotide biosynthesis makes it a useful target in the development of drugs for antiviral and anticancer chemotherapy and in immunosupressant area. Several compound with antiviral activity have been found to be inhibitors of IMPDH. For example, ribavirin, a competitive inhibitor of IMPDH, has broad spectrum antiviral activities against DNA and RNA viruses. (omitted)

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