Biyoinformatik ve Genetik Bölümü Koleksiyonu

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Citation - WoS: 2
Citation - Scopus: 3
Aryl Butenoic Acid Derivatives as a New Class of Histone Deacetylase Inhibitors: Synthesis in Vitro Evaluation and Molecular Docking Studies
(Scientific Technical Research Council Turkey-Tubitak, 2014) Esiyok, Peruze Ayhan; Seven, özlem; Eymur, Guluzar; Tatar, Gamze Bora; Erden, Didem Dayangaç; Yelekçi, Kemal; Yurter, Hayat; Demir, Ayhan S.
New aryl butenoic acid derivatives have been synthesized by combining hydroxy- or methoxy-substituted phenyl rings as the capping group with a double bond in the short linker as well as metal binding groups enoic ester and salts bearing either methyl or morpholine. These compounds have been shown to possess promising histone deacetylase inhibition activities via in vitro fluorometric assay and molecular docking studies.
Citation - WoS: 22
Citation - Scopus: 23
Critical Exponents of Gelation and Conductivity in Polyacrylamide Gels Doped by Multiwalled Carbon Nanotubes
(Taylor & Francis Ltd, 2010) Aktas, Demet Kaya; Evingür, Gülşen Akin; Pekcan, Önder
Polyacrylamide (PAM) doped by multiwalled carbon nanotube (MWNT) gels were prepared with different amounts of MWNTs varying in the range between 0.1 and 15 wt%. The PAM-MWNT composite gels were characterized by the steady state fluorescence technique (SSF). The alternative electrical conductivity (AC) of PAM-MWNT composite gels was measured by the dielectric spectroscopy technique. Observations around the gel point t(gel) for PAM-MWNTs composite gels showed that the gel fraction exponent beta obeyed the percolation result. The critical exponent r of AC electrical conductivity for the composite PAM-MWNT gel was also measured and found to be about 2.0 which agrees with a random resistor network. (C) Koninklijke Brill NV Leiden 2010
Citation - WoS: 15
Citation - Scopus: 17
Crystallographic Structure Versus Homology Model: a Case Study of Molecular Dynamics Simulation of Human and Zebrafish Histone Deacetylase 10
(Taylor & Francis, 2020) Uba, Abdullahi İbrahim; Yelekçi, Kemal
Histone deacetylase (HDAC) 10 has been implicated in the pathology of various cancers and neurodegenerative disorders, making the discovery of novel inhibitors of the isoform an important endeavor. However, the unavailability of crystallographic structure of human HDAC10 (hHDAC10) hinders structure-based drug design effort. Previously, we reported the homology modeled structure of human HDAC10 built using the crystallographic structure of Danio rerio (zebrafish) HDAC10 (zHDAC10) (Protein Data Bank (PDB) ID; 5TD7, released on 24 May 2017) as a template. Here, in continuation with our study, both hHDAC10 and zHDAC10, and their respective complexes with trichostatin A (TSA), quisinostat, and the native ligand (in 5TD7), 7-[(3-aminopropyl)amino]-1,1,1-trifluoroheptane-2,2-diol (PDB ID; FKS) were submitted to 100 ns-long unrestrained molecular dynamics (MD) simulations. Comparative analyses of the MD trajectories revealed that zHDAC10 and its complexes displayed higher stability than hHDAC10 and its corresponding complexes over time. Nonetheless, docking of active and inactive set molecules revealed that more reliable conformations of hHDAC10 could be obtained at an extended time period. This study may shed more light on the reliability of hHDAC10 modeled structure for use in selective inhibitor design.Communicated by Ramaswamy H. Sarma.
Citation - WoS: 6
Citation - Scopus: 8
The Design of Potent Hiv-1 Integrase Inhibitors by a Combined Approach of Structure-Based Virtual Screening and Molecular Dynamics Simulation
(Taylor & Francis Ltd, 2018) Samorlu, Augustine S.; Yelekçi, Kemal; Uba, Abdullahi Ibrahim
Bu araştırmanın amacı, AIDS olarak bilinen insan bağışıklık sistemine etki eden, duraksamayan ve depresif bir hastalığa neden olan HIV-1'in tedavisi için potansiyel inhibitörleri elde etmektir. HIV-1 integraz inhibitörleri, HIV-1 enfeksiyonunun tedavisinde çok önemlidir. İntegraz enziminin (IN) inhibe edilmesi HIV-1 virüsünün çoğalma işleminin sonlandırılmasına neden olur. Böylece yaşam döngüsüne son verir. Bu inhibitörleri elde etmek için bilgisayar destekli in silico yaklaşım kullanılmıştır. Temelde, Otava Kimya Kütüphanesi tarandı ve inhibitör tasarımında kullanılan sistematik yaklaşımlar uygulandı, böylece dört güçlü integraz inhibitörü bulundu. İnhibitörlerin enzime bağlanma değerleri PyRx ve AutoDock 4.2 doklama programları kullanılarak gerçekleştirildi. Çalışmada bir kimyasalın güçlü bir inhibitör olabilmesi için hesaplanan serbest bağ enerjisi = -8.00 kcal / mol veya daha az olması ve integrazın aktif bölgesinde bulunan 3 önemli amino asidinden herhangi biri ile de etkileşimde bulunması kriterine uyulmuştur. Discovery Studio Visualizer, inhibitörlerin yapısını çizmekte, inhibitörü komplekslerinin resimlerini üretmekte, enzim ve inhibitör arasındaki etkileşimin türünü belirlememizi sağlayan 2D ve 3D yapıları görüntülemek için kullanıldı. Elde edilen dört güçlü inhibitörden, kendimizin tasarladığı moleküllerden (Ki= 652.83 nanomolar bir ve bağlanma serbest enerjisi -8.44kcal / mol), kalan üç inhibitörde, Otava Kimya Kütüphanesi'nde tarandı ve Otava koduyla parantez içerisinde listelenmiştir. Bunların inhibisyon sabiti ve bağlanma enerjileri sırasıyla; 107320240, Ki=131.7nm, -9.39kcal/ mol; 109750115, Ki= 44.19nm, -10.03kcal / mol; 111150115 Ki = 395.19nm, -8.74kcal / mol olarak bulunmuştur.
Citation - WoS: 6
Citation - Scopus: 11
Design, Synthesis and Hmao Inhibitory Screening of Novel 2-Pyrazoline Analogues
(Bentham Science Publ Ltd, 2017) Evranos-Aksöz, Begüm; Uçar, Gülberk; Yelekçi, Kemal
Aim and Objective: MAO inhibitors have a significant effect on the nervous system since they act in regulation of neurotransmitter concentrations. Neurotransmitter levels are critical for a healthy nervous system. MAO inhibitors can be used in the treatment of neurological disorders such as depression, Parkinson's disease and Alzheimer's disease, as the increase or decrease of some neurotransmitter concentrations is associated with these neurological disorders. This study was conducted to discover new and active MAO inhibitor drug candidates. Materials and Methods: New pyrazoline derivatives have been designed with the molecular docking approach and interactions of our compounds with the MAO enzyme have been investigated using the Autodock 4.2 program. The designed pyrazoline derivative compounds were synthesized by the reaction of the chalcones and hydrazides in ethanol. hMAO inhibitory activities of the newly synthesized compounds were investigated by fluorimetric method. In vitro cytotoxicity of five most potent inhibitors were tested in HepG2 cells. Results: (3-(5-bromo-2-hydroxyphenyl)-5-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5i) and (3-(2-hydroxy-4-methoxy phenyl)-5-p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5l) inhibited hMAO-A more potently than moclobemide (Ki values are 0.004 +/- 0.001 and 0.005 +/- 0.001, respectively). The same two compounds, 5i and 5l, inhibited hMAO-A more selectively than moclobemide (SI values are 5.55x10(-5) and 0.003, respectively). Both of these compounds were found non toxic at 1 mu M, 5 mu M and 25 mu M concentrations. Conclusion: Two of the newly synthesized compounds, (3-(5-bromo-2-hydroxyphenyl)-5-(4-methoxyphenyl)- 4,5-dihydropyrazol-1-yl)(phenyl) methanone and (3-(2-hydroxy-4-methoxy phenyl)5- p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone were found to be promising MAO-A inhibitors due to their high inhibitory potency, high selectivity and low toxicity.
Citation - WoS: 7
Citation - Scopus: 7
Design, Synthesis and in Vitro Cytotoxic Activity of New 6,9-Disubstituted Purine Analogues
(Slovensko Kemijsko Drustvo, 2020) Kuçükdumlu, Aslıgül; Tunçbilek, Meral; Bilget Güven, Ebru; Atalay, Rengül Çetin
A series of new 6,9-disubstituted purine analogs with 4-substituted piperazine at C-6 and 4-substituted benzyl at N-9 were designed and synthesized in four steps. All synthesized compounds (7-26) were screened initially for their in vitro anticancer activity on Huh7 liver, HCT116 colon and MCF7 breast carcinoma cell lines. Cytotoxic bioactivity studies revealed that all compounds screened, with compound 19 being the exception, were found to have promising cytotoxic activities at IC50 range of 0.05-21.8 mu M against cancer cells Huh7, HCT116 and MCF7. Among the prepared purine analogs, two of them (12 and 22) exhibited excellent cytotoxic activities, with IC50 0.08-0.13 mu M, on Huh7 cells comparable to camptothecin (CPT) and better than cladribine, fludarabine and 5-FU. Afterwards, the evaluation of cytotoxicity of the most potent purine analogs was screened against further hepatocellular cancer (HCC) cell lines. The 6-(4-(4-trifluoromethylphenyl)piperazine (12) and 6-(4-(3,4-dichlorophenyl)piperazine analogs (25) displayed a significant IC50 values (IC50 < 0.1-0.13 mu M) comparable to CPT and better cytotoxic bioactivity when compared with 5-FU, cladribine and fludarabine on HCC cells (Huh7 and HepG2).
Citation - WoS: 39
Citation - Scopus: 41
A Docking Study Using Atomistic Conformers Generated Via Elastic Network Model for Cyclosporin A/Cyclophilin A Complex
(Taylor & Francis Inc, 2009) Akten, Ebru Demet; Cansu, Sertan; Doruker, Pemra
Anisotropic network model is used to generate a set of distinct conformations for cylophilin A (CypA). The native structure is deformed to different extents along each of the lowest-frequency modes (first 7 modes) both in negative and positive directions. Each node of the elastic network represents either a single atom in the high-resolution model or a single residue in the low-resolution model. Realistic conformations with energies close to or lower than the crystal structure and with satisfactory internal geometry are recovered by energy minimization using implicit solvation model. These conformations are then used for ensemble docking to the ligand cyclosporin A for both a further test of accuracy of generated conformers and exploration of different binding modes. Higher number of correctly docked ligands are obtained for conformations with low deformation factors as a result of lower root mean square distances with respect to crystal structure. Yet Surprisingly the lowest binding energy is obtained for one of the highly deformed conformations as a result of its special contact with arginine side chain oriented towards binding site. Considering the fact that the cyclic ligand's backbone and protein's side chains are held rigid during docking the conformers generated by high- and low-resolution elastic network models are almost equally successful in providing the correct binding mode. The shape of the binding pocket that incorporates crucial interaction sites for hydrogen bond formation is found to be another important determining factor for the success of the dock. Also the small backbone variations of a few angstrom ngstroms in magnitude at the loop regions surrounding the binding pocket can cause amino acids' side chains to be displaced by magnitudes of up to 10 angstrom and therefore have a strong influence on the efficiency of the conformational search during docking.
Docking-Based Virtual Screening for Potential Activity Against Bacterial Pyruvate Kinase
(Springer, 2017) Ergün, Çağla; Akten, Ebru Demet; Doruker, Pemra
[Abstract Not Available]
Citation - WoS: 240
Citation - Scopus: 288
Drug Repurposing for Coronavirus (covid-19): in Silico Screening of Known Drugs Against Coronavirus 3cl Hydrolase and Protease Enzymes
(TAYLOR & FRANCIS LTD, 2020) Elmezayen, Ammar D.; Al-Obaidi, Anas; Sahin, Alp Tegin; Yelekçi, Kemal
In December 2019, COVID-19 epidemic was described in Wuhan, China, and the infection has spread widely affecting hundreds of thousands. Herein, an effort was made to identify commercially available drugs in order to repurpose them against coronavirus by the means of structure-based virtual screening. In addition, ZINC15 library was used to identify novel leads against main proteases. Human TMPRSS2 3D structure was first generated using homology modeling approach. Our molecular docking study showed four potential inhibitors against Mpro enzyme, two available drugs (Talampicillin and Lurasidone) and two novel drug-like compounds (ZINC000000702323 and ZINC000012481889). Moreover, four promising inhibitors were identified against TMPRSS2; Rubitecan and Loprazolam drugs, and compounds ZINC000015988935 and ZINC000103558522. ADMET profile showed that the hits from our study are safe and drug-like compounds. Furthermore, molecular dynamic (MD) simulation and binding free energy calculation using the MM-PBSA method was performed to calculate the interaction energy of the top-ranked drugs. Communicated by Ramaswamy H. Sarma Keywords
Citation - WoS: 4
Citation - Scopus: 3
Drying of Polyacrylamide-Multiwalled Carbon Nanotube (mwnt) Composites With Various Mwnts Contents: a Fluorescence Study
(Walter De Gruyter Gmbh, 2013) Evingür, Gülşen Akin; Pekcan, Önder
We studied the drying of polyacrylamide (PAAm)-multiwalled carbon nanotube (MWNT) composites prepared by free radical crosslinking copolymerization in water with a steady state fluorescence technique. Composite gels were prepared at room temperature with pyranine (Py) doped as a fluorescence probe. Drying experiments were performed in air at various MWNT contents by real time monitoring of the Py fluorescence intensity (I) which increased as the drying proceeded. The Stern-Volmer equation combined with the moving boundary diffusion model was used to explain the behavior of I during drying. It was observed that the desorption coefficient (D) increased as the temperature increased. Drying energies (Delta E) were measured for the drying processes for each MWNT content gel by using fluorescence gravimetrical and volumetric methods. It is understood that Delta E values decrease by increasing MWNT content until 1 wt % MWNT and then increase above the level of this threshold value. The energy of drying is strongly correlated with the MWNT content in the composite. Delta E drops to its lowest value at which conducting cluster starts to appear.
Citation - WoS: 11
Citation - Scopus: 14
Effect of Multiwalled Carbon Nanotube (mwnt) on the Behavior of Swelling of Polyacrylamide-Mwnt Composites
(Sage Publications Ltd, 2014) Evingür, Gülşen Akin; Pekcan, Önder
The purpose of this paper is to discuss the role of multiwalled carbon nanotube in the swelling of polyacrylamide-multiwalled carbon nanotube composites. Swelling experiments were performed in water at various temperatures by real-time monitoring of the decrease in pyranine (Py) and emission light intensity (I-em). The Stern-Volmer equation is modified for low-quenching efficiencies to interpret the behavior of pyranine intensity during the swelling of polyacrylamide-multiwalled carbon nanotube composites. The Li-Tanaka equation was used to determine the swelling time constants tau and cooperative diffusion coefficients D from fluorescence intensity weight and volume variations of the composite at various temperatures. It was observed that when tau decreased naturally D increased by increasing temperatures.
Citation - WoS: 12
Citation - Scopus: 14
Elastic Percolation of Swollen Polyacrylamide (paam)-Multiwall Carbon Nanotubes Composite
(Taylor & Francis Ltd, 2012) Evingür, Gülşen Akin; Pekcan, Önder
Polyacrylamide (PAAm)-multiwalled carbon nanotube (MWNT) composites were prepared via free radical cross-linking copolymerization with different amounts of MWNTs varying in the range between 0.1 and 50 wt%. The mechanical properties of swollen PAAm-MWNT composites were characterized by the tensile testing technique. A small content of embedded nanotubes dramatically changes the compressive elastic modulus of the composites. Compressive elastic modulus dramatically increases up to 1wt% MWNT on increasing nanotube content and then decreases presenting a critical MWNT value indicating that there is a sudden change in the material elasticity. The critical exponent y of elasticity below the critical MWNT content 1 wt% is found to be 0.58 which is consistent with the suggestions of percolation in the superelastic percolation network for PAAm-MWNT composite.
Citation - WoS: 17
Citation - Scopus: 18
Electrical and Optical Percolations in Pmma/Gnp Composite Films
(Taylor & Francis Ltd, 2018) Arda, Ertan; Mergen, Omer Bahadir; Pekcan, Önder
Effects of graphene nanoplatelet (GNP) addition on the electrical conductivity and optical absorbance of poly(methyl methacrylate)/graphene nanoplatelet (PMMA/GNP) composite films were studied. Optical absorbance and two point probe resistivity techniques were used to determine the variations of the optical and electrical properties of the composites respectively. Absorbance intensity A and surface resistivity R-s of the composite films were monitored as a function of GNP mass fraction (M) at room temperature. Absorbance intensity values of the composites were increased and surface resistivity values were decreased by increasing the content of GNP in the composite. Electrical and optical percolation thresholds of composite films were determined as M-sigma = 27.5 wt.% and M-op = 26.6 wt.% respectively. The conductivity and the optical results were attributed to the classical and site percolation theories respectively. Optical ((op)) and electrical ((sigma)) critical exponents were calculated as 0.40 and 1.71 respectively.
Citation - WoS: 4
Citation - Scopus: 3
Electrical Optical and Fluorescence Percolations in P(vac-co-bua)/Mwcnt Composite Films
(Taylor & Francis Ltd, 2013) Arda, Ertan; Kara, Selim; Pekcan, Önder
Effects of multiwall carbon nanotube (MWCNT) addition on the electrical conductivities optical transparencies and fluorescence emissions of poly(vinyl acetate-co-butyl acrylate) (P(VAc-co-BuA))/MWCNT composite films were studied. Optical transmission fluorescence emission and two point probe resistivity techniques were used to determine the variations of the optical fluorescence and electrical properties of the composites respectively. Transmitted photon intensity (I-tr) fluorescence emission intensity (I-fl) and surface resistivity ((s)) of the composite films were monitored as a function of MWCNT mass fraction (M) at room temperature. All these measured quantities of the composites were decreased by increasing the content of MWCNT in the composite. The conductivity and the optical results were attributed to the classical and site percolation theories respectively. The fluorescence results however possessed both the site and classical percolation theories at low and high MWCNT content regions respectively.
Citation - WoS: 5
Citation - Scopus: 5
Epidemic Models for Phase Transitions: Application To a Physical Gel
(Taylor & Francis Ltd, 2017) Bilge, Ayşe Hümeyra; Pekcan, Önder; Kara, Selim; Öğrenci, Arif Selçuk
Carrageenan gels are characterized by reversible sol-gel and gel-sol transitions under cooling and heating processes and these transitions are approximated by generalized logistic growth curves. We express the transitions of carrageenan-water system as a representative of reversible physical gels in terms of a modified Susceptible-Infected-Susceptible epidemic model as opposed to the Susceptible-Infected-Removed model used to represent the (irreversible) chemical gel formation in the previous work. We locate the gel point T-c of sol-gel and gel-sol transitions and we find that for the sol-gel transition (cooling) T-c > T-sg (transition temperature) i.e. T-c is earlier in time for all carrageenan contents and moves forward in time and gets closer to T-sg as the carrageenan content increases. For the gel-sol transition (heating) T-c is relatively closer to T-gs
Citation - WoS: 14
Citation - Scopus: 20
Examining the Stability of Binding Modes of the Co-Crystallized Inhibitors of Human Hdac8 by Molecular Dynamics Simulation
(Taylor & Francis Inc, 2019) Uba, Abdullahi Ibrahim; Weako, Jackson; Keskin, Özlem; Gürsoy, Attila; Yelekçi, Kemal
Histone deacetylase (HDAC) 8 has been implicated as a potential therapeutic target in a variety of cancers neurodegenerative disorders metabolic dysregulation and autoimmune and inflammatory diseases. Several nonselective HDAC inhibitors have been co-crystallized with HDAC8. Molecular dynamics (MD) studies may yield valuable information on the structural stabilities of the complexes over time as determined by various pharmacophore features of the co-crystallized inhibitors. Here using 11 unmodified X-ray crystal structures of human HDAC8 (complexes) structure-based pharmacophore models were built and clustered based on distance - a function of the number of common pharmacophore features and the root-mean-squared displacement between the matching features. Based on this information a total of seven complexes (1T64 1W22 3RQD 3SFF 3F0R 5VI6 and 5FCW) were submitted to unrestrained 50 ns-MD simulations using nanoscale MD (NAMD) software. 1T64 (HDAC8 in complex with TSA) was found to show the highest stability over time presumably because of the TSA's ability to span HDAC8 catalytic channel and form a strong ionic interaction with zinc metal ion. Other stable complexes were 1W22 3SFF 3F0R and 5FCW. However 3RQD and 5VI6 showed relative instability over 50 ns time period. This may be attributed to bulkiness of the capping groups of both largazole thiol and trapoxin A making them unable to fit well into the active site of HDAC8. They rather formed steric clashes with residues on loop regions near the entrance to the channel. Thus 1T64 and similar crystal structures may be good candidates for HDAC8 structural dynamics studies and inhibitor design. Communicated by Ramaswamy H. Sarma
Citation - WoS: 14
Citation - Scopus: 14
Exploration of the Binding Pocket of Histone Deacetylases: the Design of Potent and Isoform-Selective Inhibitors
(Tübitak, 2017) Auba, Budullahi İbrahim; Yelekçi, Kemal
Histone deacetylases (HDACs) are enzymes that act on histone proteins to remove the acetyl group and thereby regulate the chromatin state. HDACs act not only on histone protein but also nonhistone proteins that are key players in cellular processes such as the cell cycle, signal transduction, apoptosis, and more. “Classical” HDACs have been shown to be promising targets for anticancer drug design and development. However, the selectivity of HDAC inhibitors for HDAC isoforms remains the motivation of current research in this field. Here, we explored Class I HDACs and HDAC6 by sequence alignment and structural superimposition, catalytic channel extraction, and identification of critical residues involved in HDAC catalysis. Based on the general pharmacophore features of known HDAC inhibitors, we developed a library of compounds by scaffold hopping on a fragment hit identified via structurebased virtual screening of the molecular fragment library retrieved from the Otava database. Molecular docking assay revealed five of these compounds to have increased potency and selectivity for HDACs 1 and 2. Furthermore, their predicted absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties were consistent with those of drug-like compounds. With further modelingbased and experimental investigations, we believe that these findings may offer additional potential HDAC inhibitors with improved selectivity
Citation - WoS: 1
Citation - Scopus: 1
Exploring Distinct Binding Site Regions of Beta(2)-Adrenergic Receptor Via Coarse-Grained Molecular Dynamics Simulations
(Scientific Technical Research Council Turkey-Tubitak, 2013) Cakan, Sibel; Akdoğan, Ebru Demet
beta(2)-Adrenergic receptor (beta(2)AR) is a G protein-coupled receptor that is highly flexible and able to recognize a wide range of ligands through its conformational variations. Active and inactive conformations revealed by recent crystallographic experiments do not provide a complete dynamic picture of the receptor especially in the binding site. In this study molecular dynamics (MD) simulation through a residue-based coarse-grained model is used as an alternative and efficient method to explore a wider conformational search space. The system was composed of beta(2)AR embedded into a 1-palmitoyl-2-oleoyl-phosphatidylcholine membrane bilayer with surrounding water. A total of 6 mu s of simulation at constant NPT was performed for a system of 6868 coarse-grained beads. The system reached equilibrium at around 0.1 mu s. The overall 3-dimensional structure was well preserved throughout the simulation. Local residue-based fluctuations were in good agreement with fully atomistic MD simulations. Four distinct snapshots were selected and reverse-mapped to all-atom representations with around 65000 atoms. Each reverse-mapped system was later subjected to 100 ns of MD simulation for equilibration. Root mean square deviation clustering analysis yielded distinct receptor conformers for the binding site regions which were suggested to be alternative representations of the binding pocket and thus were proposed as plausible targets in docking-based virtual screening experiments for the discovery of novel antagonists.
Citation - WoS: 15
Citation - Scopus: 15
A Fluorescence Study on Swelling of Hydrogels (paam) at Various Cross-Linker Contents
(Wiley, 2009) Aktas, Demet Kaya; Evingür, Gülşen Akin; Pekcan, Önder
Disk-shaped acrylamide (AAm) gels were prepared from AAm with various NN'-methylenebisacrylamide (Bis) contents as cross-linker in the presence of ammonium persulfate as an initiator by free-radical cross-linking copolymerization in water. Polyacrylamide (PAAm) gels were dried before using for swelling experiments. Steady-state fluorescence spectrometer was employed during the swelling of PAAm hydrogels in water. Pyranine was introduced as a fluorescence probe. Fluorescence intensity of pyranine from various Bis content gel samples was measured during in situ swelling process. It was observed that fluorescence intensity decreased as swelling has proceeded. Gravimetric and volumetric experiments were also performed. The Li-Tanaka equation was used to determine the swelling time constants tau(c) and cooperative diffusion coefficients D-c from intensity weight and volume variations during the swelling processes. It was observed that swelling time constants tau(c) increased and diffusion coefficients D-c decreased as the cross-linker content was increased. (C) 2010 Wiley Periodicals Inc. Adv Polym Techn 28:215-223 2009
Citation - WoS: 10
Citation - Scopus: 10
Homology Modeling Andin Silicodesign of Novel and Potential Dual-Acting Inhibitors of Human Histone Deacetylases Hdac5 and Hdac9 Isozymes
(2020) Elmezayen, Ammar D.; Yelekçi, Kemal
Histone deacetylases (HDACs) are a group of enzymes that have prominent and crucial effect on various biological systems, mainly by their suppressive effect on transcription. Searching for inhibitors targeting their respective isoforms without affecting other targets is greatly needed. Some histone deacetylases have no crystal structures, such as HDAC5 and HDAC9. Lacking proper and suitable crystal structure is obstructing the designing of appropriate isoform selective inhibitors. Here in this study, we constructed human HDAC5 and HDAC9 protein models using human HDAC4 (PDB:2VQM_A) as a template by the means of homology modeling approach. Based on the Z-score of the built models, model M0014 of HDAC5 and model M0020 of HDAC9 were selected. The models were verified by MODELLER and validated using the Web-based PROCHECK server. All selected known inhibitors displayed reasonable binding modes and equivalent predicted Ki values in comparison to the experimental binding affinities (Ki/IC50). The known inhibitor Rac26 showed the best binding affinity for HDAC5, while TMP269 showed the best binding affinity for HDAC9. The best two compounds, CHEMBL2114980 and CHEMBL217223, had relatively similar inhibition constants against HDAC5 and HDAC9. The built models and their complexes were subjected to molecular dynamic simulations (MD) for 100 ns. Examining the MD simulation results of all studied structures, including the RMSD, RMSF, radius of gyration and potential energy suggested the stability and reliability of the built models. Accordingly, the results obtained in this study could be used for designing de novo inhibitors against HDAC5 and HDAC9. Communicated by Ramaswamy H. Sarma

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