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Computational Exploration for Lead Compounds That Can Reverse the Nuclear Morphology in Progeria
Rampogu, Shailima,Baek, Ayoung,Son, Minky,Zeb, Amir,Park, Chanin,Kumar, Raj,Lee, Gihwan,Kim, Donghwan,Choi, Yeonuk,Cho, Yeongrae,Park, Yohan,Park, Seok Ju,Lee, Keun Woo Hindawi 2017 BioMed research international Vol.2017 No.-
<P>Progeria is a rare genetic disorder characterized by premature aging that eventually leads to death and is noticed globally. Despite alarming conditions, this disease lacks effective medications; however, the farnesyltransferase inhibitors (FTIs) are a hope in the dark. Therefore, the objective of the present article is to identify new compounds from the databases employing pharmacophore based virtual screening. Utilizing nine training set compounds along with lonafarnib, a common feature pharmacophore was constructed consisting of four features. The validated Hypo1 was subsequently allowed to screen Maybridge, Chembridge, and Asinex databases to retrieve the novel lead candidates, which were then subjected to Lipinski's rule of 5 and ADMET for drug-like assessment. The obtained 3,372 compounds were forwarded to docking simulations and were manually examined for the key interactions with the crucial residues. Two compounds that have demonstrated a higher dock score than the reference compounds and showed interactions with the crucial residues were subjected to MD simulations and binding free energy calculations to assess the stability of docked conformation and to investigate the binding interactions in detail. Furthermore, this study suggests that the Hits may be more effective against progeria and further the DFT studies were executed to understand their orbital energies.</P>
Seung Yeop Baek,Na Rae Lee,Da Hye Kim,Ayoung Gu,Seong Yeol Kim,Dae-Yong Song,김동희,Hak Joo Choi,Byung-Jun Park,김인식 대한독성 유전단백체 학회 2015 Molecular & cellular toxicology Vol.11 No.2
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra pars compacta. In this study, we investigated the effects of a novel herb formula, Hepad, on PD. Dose-dependent treatment with 1-methyl-4-phenylpyridinium (MPP+) decreased the viability of SH-SY5Y cells, and Hepad inhibited the toxic effect of MPP+. Hepad blocked the production of reactive oxygen species (ROS) induced by MPP+ in SH-SY5Y cells, and suppressed the activation of caspase 9 and caspase 3 due to MPP+. A rat model of PD was generated by 6-hydroxydopamine (6-OHDA) injection into the left medial forebrain bundle (MFB) of SD rats. In D-amphetamine sulfate-induced rotational behavioral tests, Hepad administration attenuated circling behavior relative to the 6-OHDA-treated disease group. In addition, Hepad treatment significantly increased the tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta (SNpc) that had decreased in response to 6-OHDA treatment (P<0.05). OX-6 expression, which indicates the presence of microglial cells, decreased significantly after treatment of Hepad in contrast to the 6-OHDA-treated disease group (P<0.05). These results indicate that Hepad may be a useful neuroprotective material for the treatment of neurodegenerative disorders such as PD.
Effect of house dust mite on neutrophil apoptosis by cytokine secretion in lymphocytes
Lee, Na Rae,Lee, Ji-Sook,Baek, Seung Yeop,Kim, Da Hye,Gu, Ayoung,Kim, Seong Yeol,Lee, Soo Jin,Kim, In Sik THE KOREAN SOCIETY OF TOXICOGENOMICS AND TOXICOPRP 2016 MOLECULAR AND CELLULAR TOXICOLOGY Vol. No.
Although extract of Dermatophagoides farinae (DF) alone had no effect on neutrophil apoptosis, it inhibited neutrophil apoptosis in neutrophils cocultured with lymphocytes in both normal and allergic subjects. DF showed a stronger inhibition on the apoptosis of allergic neutrophils cocultured with allergic lymphocytes than that of normal neutrophils cocultured with normal lymphocytes. DF induced the secretion of IL-6, IL-8, MCP-1, and GM-CSF of the normal and allergic lymphocytes. The cytokine secretion due to DF in allergic lymphocytes is higher than in normal lymphocytes. The cytokine secretion of normal and allergic lymphocytes induced by DF was suppressed by PAR2i, a PAR2 inhibitor, LY294002, a PI3K inhibitor, AKTi, an Akt inhibitor, PD98059, an ERK inhibitor, and BAY-11-7085, an <TEX>$NF-{\kappa}B$</TEX> inhibitor. Phosphorylation of ERK induced by DF was suppressed by PAR2i, LY294002 and AKTi, and <TEX>$NF-{\kappa}B$</TEX> activity due to DF was inhibited by PAR2i, LY294002, AKTi, and PD98059.
Pharmacophore Identification for Peroxisome Proliferator-Activated Receptor Gamma Agonists
손영식,이윤호,Chanin Park,Swan Hwang,Songmi Kim,Ayoung Baek,Minky Son,서정근,Hyong-Ha Kim,이근우 대한화학회 2011 Bulletin of the Korean Chemical Society Vol.32 No.1
Peroxisome proliferator-activated receptors (PPARs) are members of nuclear receptors and their activation induces regulation of fatty acid storage and glucose metabolism. Therefore, the PPARγ is a major target for the treatment of type 2 diabetes mellitus. In order to generate pharmacophore model, 1080 known agonists database was constructed and a training set was selected. The Hypo7, selected from 10 hypotheses, contains four features: three hydrogen-bond acceptors (HBA) and one general hydrophobic (HY). This pharmacophore model was validated by using 862 test set compounds with a correlation coefficient of 0.903 between actual and estimated activity. Secondly, CatScramble method was used to verify the model. Hence, the validated Hypo7 was utilized for searching new lead compounds over 238,819 and 54,620 chemical structures in NCI and Maybridge database, respectively. Then the leads were selected by screening based on the pharmacophore model, predictive activity, and Lipinski’s rules. Candidates were obtained and subsequently the binding affinities to PPARγ were investigated by the molecular docking simulations. Finally the best two compounds were presented and would be useful to treat type 2 diabetes.
Rampogu, Shailima,Parate, Shraddha,Parameswaran, Saravanan,Park, Chanin,Baek, Ayoung,Son, Minky,Park, Yohan,Park, Seok Ju,Lee, Keun Woo Elsevier 2019 Computational biology and chemistry Vol.83 No.-
<P><B>Abstract</B></P> <P>Breast cancer is one of the major impediments affecting women globally. The ATP-dependant heat shock protein 90 (Hsp90) forms the central component of molecular chaperone machinery that predominantly governs the folding of newly synthesized peptides and their conformational maturation. It regulates the stability and function of numerous client proteins that are frequently upregulated and/or mutated in cancer cells, therefore, making Hsp90 inhibition a promising therapeutic strategy for the development of new efficacious drugs to treat breast cancer. In the present <I>in silico</I> investigation, a structure-based pharmacophore model was generated with hydrogen bond donor, hydrogen bond acceptor and hydrophobic features complementary to crucial residues Ala55, Lys58, Asp93, Ile96, Met98 and Thr184 directed at inhibiting the ATP-binding activity of Hsp90. Subsequently, the phytochemical dataset of 3210 natural compounds was screened to retrieve the prospective inhibitors after rigorous validation of the model pharmacophore. The retrieved 135 phytocompounds were further filtered by drug-likeness parameters including Lipinski’s rule of five and ADMET properties, then investigated via molecular docking-based scoring. Molecular interactions were assessed using Genetic Optimisation for Ligand Docking program for 95 drug-like natural compounds against Hsp90 along with two clinical drugs as reference compounds – Geldanamycin and Radicicol. Docking studies revealed three phytochemicals are better than the investigated clinical drugs. The reference and hit compounds with dock scores of 48.27 (Geldanamycin), 40.90 (Radicicol), 73.04 (Hit1), 72.92 (Hit2) and 68.12 (Hit3) were further validated for their binding stability through molecular dynamics simulations. We propose that the non-macrocyclic scaffolds of three identified phytochemicals might aid in the development of novel therapeutic candidates against Hsp90-driven cancers.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Natural compounds are identified as Hsp90 inhibitors. </LI> <LI> These compounds show stable interactions with key residues. </LI> <LI> Non-quinone containing compounds were discovered by structure based pharmacophore modelling. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Nagakumar Bharatham,Kavitha Bharatham,이윤호,Songmi Kim,Prettina Lazar,Ayoung Baek,Chanin Park,엄희성,하현준,Sae Young Yun,이원구,Sunghoon Kim,이근우 대한화학회 2010 Bulletin of the Korean Chemical Society Vol.31 No.3
Aminoacyl-tRNA synthetases (aaRSs) play vital roles in protein biosynthesis of living organisms and are interesting antibacterial drug targets. In order to find out new inhibitor candidate molecules as antibacterial agent, the binding modes of the candidate molecules were investigated at the active sites of aaRSs by molecular docking study. The docking simulations were performed with 48 compounds from four different scaffolds into the eight different aaRSs. The results show that scaffolds 3 and 4 compounds have consistently better binding capabilities, specifically for HisRS (E. coli) and IleRS (S. aureus). The binding modes of the best compounds with the proteins were well compatible with those of two ligands in crystal structures. Therefore, we expect that the final compounds we present may have reasonable aaRS inhibitory activity.
New Constitutively Active Phytochromes Exhibit Light-Independent Signaling Activity
Jeong, A-Reum,Lee, Si-Seok,Han, Yun-Jeong,Shin, Ah-Young,Baek, Ayoung,Ahn, Taeho,Kim, Min-Gon,Kim, Young Soon,Lee, Keun Woo,Nagatani, Akira,Kim, Jeong-Il American Society of Plant Biologists 2016 PLANT PHYSIOLOGY - Vol.171 No.4
<P>Plant phytochromes are photoreceptors that mediate a variety of photomorphogenic responses. There are two spectral photoisomers, the red light-absorbing Pr and far-red light-absorbing Pfr forms, and the photoreversible transformation between the two forms is important for the functioning of phytochromes. In this study, we isolated a Tyr-268-to-Val mutant of Avena sativa phytochrome A (AsYVA) that displayed little photoconversion. Interestingly, transgenic plants of AsYVA showed light-independent phytochrome signaling with a constitutive photomorphogenic (cop) phenotype that is characterized by shortened hypocotyls and open cotyledons in the dark. In addition, the corresponding Tyr-303-to-Val mutant of Arabidopsis (Arabidopsis thaliana) phytochrome B (AtYVB) exhibited nuclear localization and interaction with phytochrome-interacting factor 3 (PIF3) independently of light, conferring a constitutive photomorphogenic development to its transgenic plants, which is comparable to the first constitutively active version of phytochrome B (YHB; Tyr-276-to-His mutant). We also found that chromophore ligation was required for the light-independent interaction of AtYVB with PIF3. Moreover, we demonstrated that AtYVB did not exhibit phytochrome B activity when it was localized in the cytosol by fusion with the nuclear export signal and that AsYVA exhibited the full activity of phytochrome A when localized in the nucleus by fusion with the nuclear localization signal. Furthermore, the corresponding Tyr-269-to-Val mutant of Arabidopsis phytochrome A (AtYVA) exhibited similar cop phenotypes in transgenic plants to AsYVA. Collectively, these results suggest that the conserved Tyr residues in the chromophore-binding pocket play an important role during the Pr-to-Pfr photoconversion of phytochromes, providing new constitutively active alleles of phytochromes by the Tyr-to-Val mutation.</P>
In Sik Kim,Mi Ae Im,Na Rae Lee,Seung Yeop Baek,Beom Seok Park,Ayoung Gu,Da Hye Kim,Ji-Sook Lee 대한독성 유전단백체 학회 2015 Molecular & cellular toxicology Vol.11 No.2
House dust mite is a major allergen in allergic diseases such as asthma. In this study, we investigated the effects of house dust mite on constitutive eosinophil apoptosis in normal and asthmatic subjects. We classified asthmatic subjects into those with atopic and non-atopic asthma depending on the presence of DP-specific IgE or/and DF-specific IgE in serum. Both blood and bronchoalveolar lavage fluid (BALF) eosinophils in atopic asthma were elevated when compared with normal and non-atopic eosinophils. Dermatophagoides pteronissinus extract (DP) inhibited constitutive eosinophil apoptosis of atopic asthmatic subjects, but not that of normal and non-atopic subjects. DF had no effect on eosinophil apoptosis in normal and asthmatic subjects. The anti-apoptotic effects of DP were not altered by E64, a cysteine protease inhibitor, or aprotinin, a serine protease inhibitor, and Der p1 and Der p 2 had no effect on eosinphil apoptosis of normal and asthmatic patients, including atopic and not-atopic patients. Anti-apoptotic signaling mediated by DP in atopic asthma was associated with the TLR4/PI3K/Akt/ERK/NF- κB pathway. Activation of procaspase 3 and procaspase 9 was delayed by DP stimulation. Our results indicate that DP induces eosinophilic inflammation by inhibiting eosinophil apoptosis, and that the inhibitory effect is associated with exposure of asthma subjects to DP. A better understanding of the difference between atopic and non-atopic asthma will help elucidate the pathogenesis and develop methods for treatment of asthma