• Title, Summary, Keyword: inhibitor binding

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Virtual Screening of Penicillin-derived Inhibitors for the Metallo-β-lactamase from Bacillus cereus

  • Lee, Jong-Sun;White, Ethan;Kim, Sang-Gon;Kim, Sung-Kun
    • Bulletin of the Korean Chemical Society
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    • v.31 no.12
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    • pp.3644-3652
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    • 2010
  • The metallo-$\beta$-lactamases ($M{\beta}Ls$) are clinically significant enzymes which readily hydrolyze most $\beta$-lactam antibiotics. Discovering potential inhibitors for the $M{\beta}Ls$ is an expensive, time consuming endeavor. Virtual screening can sieve out inhibitor candidates with incompatible features prior to synthesis, decreasing these costs. Using Autodock 4.0, the binding locations and energies of four previously-studied potential inhibitors and four additional compounds obtained from the National Cancer Institute (NCI) database were computationally calculated. Based on the docking models of these eight compounds, we then designed several hypothetical inhibitor structures, compounds A through F, and performed their respective docking experiments. The docking results for compound F showed that it binds to the zinc containing active sites with a lowest predicted binding energy of -6.70 kcal/mol, suggesting F is the most likely potential $M{\beta}L$ inhibitor.

Characterization of Binding Mode of the Heterobiaryl gp120 Inhibitor in HIV-1 Entry: A Molecular Docking and Dynamics Simulation Study

  • Gadhe, Changdev G.;Kothandan, Gugan;Cho, Seung Joo
    • Bulletin of the Korean Chemical Society
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    • v.34 no.8
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    • pp.2466-2472
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    • 2013
  • Human immunodeficiency virus type-1 (HIV-1) is a causative agent of Acquired immunodeficiency syndrome (AIDS), which has affected a large population of the world. Viral envelope glycoprotein (gp120) is an intrinsic protein for HIV-1 to enter into human host cells. Molecular docking guided molecular dynamics (MD) simulation was performed to explore the interaction mechanism of heterobiaryl derivative with gp120. MD simulation result of inhibitor-gp120 complex demonstrated stability. Our MD simulation results are consistent with most of the previous mutational and modeling studies. Inhibitor has an interaction with the CD4 binding region. Van der Waals interaction between inhibitor and Val255, Thr257, Asn425, Met426 and Trp427 were important. This preliminary MD model could be useful in exploiting heterobiaryl-gp120 interaction in greater detail, and will likely to shed lights for further utilization in the development of more potent inhibitors.

Binding Free Energy Simulations of the HIV-1 Protease and Hydroxyethylene Isostere Inhibitors

  • Won, Yeong Do
    • Bulletin of the Korean Chemical Society
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    • v.21 no.12
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    • pp.1207-1212
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    • 2000
  • The free energy simulation technique is used to evaluate the relative binding affinity of a set of hydroxyethylene isostere inhibitors of the HIV-1 protease. The binding reactions and an alchemical mutation construct the thermodynamic cycle, which reduces the free energy difference of the binding interactions into that of the alchemical processes. In the alchemical process, a methyl group is mutated into a hydrogen atom. Albeit the change is a small perturbation to the inhibitor-protease complex, it results in 25 fold difference in the binding constants. The simulation reproduces the experimentally measured binding affinities within 2% of the free energy difference. The protonation state of the catalytic aspartic acid residues is also investigated through the free energy simulations.

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Alpha-alkylcysteines as Inhibitors for Carboxypeptidase A. Synthesis, Evaluation, and Implication for Inhibitor Design Strategy

  • Lee, Hyun-Soo;Kim, Dong-H.
    • Bulletin of the Korean Chemical Society
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    • v.23 no.4
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    • pp.593-597
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    • 2002
  • (R,S)- and (R)-2-Benzylcysteine (1) and (R,S)-2-phenethylcysteine (2) were synthesized and evaluated as inhibitors for carboxypeptidase A (CPA) with the expectation that these compounds exhibit improved inhibitory activities over 2-benzyl-3-mercaptopropanoic acid (BMPA), a potent CPA competitive inhibitor, possibly having additional interactions of their amino group with the carboxylate of Glu-270 of the enzyme upon binding to CPA. Contrary to the expectation, however, the CPA inhibitory potencies of these compounds were found to be much reduced compared with that of BMPA, suggesting that the amino group in the inhibitors rather exerts steric hindrance in binding of these inhibitors to CPA.

Inhibitor of DNA Binding Protein (Id)1 and Id2 mRNA Expression on Folliculogenesis in Rat Ovary (랫드 난소에서 난포 발달에 따른 DNA 결합 단백질 억제인자 (Inhibitor of DNA Binding Protein) Id1 and Id2 mRNA 발현)

  • Hwang, Seong-Soo;Lee, Pyung-Hee;Ko, Yeoung-Gyu;Yang, Byoung-Chul;Seong, Hwan-Hoo;Min, Kwan-Sik;Yoon, Jong-Taek
    • Journal of Embryo Transfer
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    • v.23 no.3
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    • pp.183-187
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    • 2008
  • This study was conducted to analyze the expression pattern of inhibitor of DNA binding proteins (Id)1 and Id2 mRNA on folliculogenesis in rat ovary. The ovaries were obtained from 27 days old Sprague-Dawley rat, fixed, dehydrated, and paraffin embedded. For in situ hybridization, anti-sense and sense Idl and Id2 cRNA probes were prepared and applied to the ovarian section. The ovarian sections were coated with NTB-2 emulsion. After that, the slides were developed and counterstained with hematoxylin and eosin staining. In oocytes, the hybridizational signals of Id1 mRNA were strong in primordial and primary follicles, however, there were no signals in that of atretic or preovulatory follicles. The Id2 mRNA signals were also strong in the oocytes of primordial, primary and secondary follicles. Interestingly, the Id2 mRNA was expressed specifically granulosa cells, but nor in oocyte or theca cells in dominant and preovulatory follicles. Based on these results, Id1 and Id2 mRNA was expressed specifically at follicle stages and follicular tissue and might be closely related with follicle development.

Cellular activities and docking studies of eckol isolated from Ecklonia cava (Laminariales, Phaeophyceae) as potential tyrosinase inhibitor

  • Lee, Seung-Hong;Kang, Sung-Myung;Sok, Chang Hyun;Hong, Jin Tae;Oh, Jae-Young;Jeon, You-Jin
    • ALGAE
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    • v.30 no.2
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    • pp.163-170
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    • 2015
  • Tyrosinase inhibitors are an important component of cosmetic products. Our previous studies have proposed that eckol isolated from the brown alga Ecklonia cava, can be explored as a tyrosinase inhibitor. However, cellular activities and mechanism of action of eckol remain unknown. Therefore, the current study analyzed the eckol binding modes using the crystal structure of Bacillus megaterium tyrosinase. The effects of eckol on melanin synthesis induced by ${\alpha}$-melanocyte stimulating hormone in B16F10 melanoma cells were also investigated. We predicted the 3D structure of tyrosinase and used a docking algorithm to simulate binding between tyrosinase and eckol. These molecular modeling studies were successful (calculated binding energy value, $-115.84kcal\;mol^{-1}$) and indicated that eckol interacts with Asn205, His208, and Arg209. Furthermore, eckol markedly inhibited tyrosinase activity and melanin synthesis in B16F10 melanoma cells. We also found that eckol decreased the expression of tyrosinase, tyrosinase-related protein (TRP) 1, and TRP2. These results indicate that eckol is a potent inhibitor of melanogenesis, and this finding may be useful for the development of novel pharmaceutical and cosmetic agents.

Mutagenic Analysis of hPNMT Confirms the Importance of Lys57 and the Inhibitor Binding Site

  • Jeong, Ki-Woong;Kang, Dong-Il;Lee, Jee-Young;Kim, Yang-Mee
    • Bulletin of the Korean Chemical Society
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    • v.32 no.2
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    • pp.455-458
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    • 2011
  • In previous report, with the aid of receptor-oriented pharmacophore-based in silico screening, we characterized three novel hPNMT inhibitors (YPN010, YPN016, and YPN017) and proposed that the hydrogen bonding interaction between inhibitors and side chain of Lys57 is very important to inhibitory activity of hPNMT. To confirm the importance of Lys57, mutant with substitution of Lys57 with Ala was cloned and binding study was performed for a K57A mutant of hPNMT using STD-NMR and fluorescence experiments. The binding constants for three novel inhibitors with mutant hPNMT were dramatically decreased compared to those with wild-type protein. K57A mutant-induced conversion of noradrenaline to adrenaline was suppressed about 95 % compared to wild-type hPNMT. Mutagenic analysis using a K57A mutant confirmed the importance of the Lys57 residue in binding of the inhibitor candidate to hPNMT as well as enzymatic activity of hPNMT, implying that these results are consistent with our binding model.

Identification of a Deoxyribonuclease I Inhibitor from a Phage-Peptide Library

  • Choi, Suk-Jung;Sperinde, Jeffrey J.;Szoka, Francis C. Jr.
    • Molecules and Cells
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    • v.19 no.1
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    • pp.54-59
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    • 2005
  • Deoxyribonuclease I (DNase I) is a divalent cation dependent endonuclease and thought to be a significant barrier to effective gene delivery. The only known DNase I-specific inhibitor is monomeric actin which acts by forming a 1:1 complex with DNase I. Its use, however, is restricted because of tendency to polymerize under certain conditions. We screened two random phage peptide libraries of complexity $10^8$ and $10^9$ for DNase I binders as candidates for DNase I inhibitors. A number of DNase I-binding peptide sequences were identified. When these peptides were expressed as fusion proteins with Escherichia coli maltose binding protein, they inhibited the actin-DNase I interaction ($IC_{50}=0.1-0.7{\mu}M$) and DNA degradation by DNase I ($IC_{50}=0.8-8{\mu}M$). Plasmid protection activity in the presence of DNase I was also observed with the fusion proteins. These peptides have the potential to be a useful adjuvant for gene therapy using naked DNA.

Development of the Phage Displayed Peptide as an Inhibitor of MCP-1 (Monocyte Chemoattractant Protein-1)-mediated Angiogenesis

  • Jeong, Sun-Joo
    • Proceedings of the Microbiological Society of Korea Conference
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    • pp.132-134
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    • 2005
  • The CC chemokine, monocyte chemoattractant protein-1 (MCP-1), plays a crucial role in the initiation of atherosclerosis and has direct effects that promote angiogenesis. To develop a specific inhibitor for MCP-1-induced angiogenesis, we performed in vitro selection employing phage display random peptide libraries. Most of the selected peptides were found to be homologous to the second extracellular loops of CCR2 and CCR3. We synthesized the peptide encoding the homologous sequences of the receptors and tested its effect on the MCP-1 induced angiogenesis. Surface Plasmon Resonance measurements demonstrated specific binding of the peptide to MCP-1 but not to the other homologous protein, MCP-3. Flow cytometry revealed that the peptide inhibited the MCP-1 binding to THP-1 monocytes. Moreover, CAM and rat aortic ring assays showed that the peptide inhibited MCP-1 induced angiogenesis. Our observations indicate that the MCP-1-binding peptide exerts its anti-angiogenic effect by interfering with the interaction between MCP-1 and its receptor.

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