Biyoinformatik ve Genetik Bölümü Koleksiyonu
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Article Citation Count: 18Absolute configuration and biological profile of pyrazoline enantiomers as MAO inhibitory activity(Wiley, 2019) Yelekçi, Kemal; Sarıgül, Sevgi; Bultinck, Patrick; Herrebout, Wouter; Doğan, İlknur; Yelekçi, Kemal; Uçar, Gülberk; Kelekçi, Nesrin GökhanA new racemic pyrazoline derivative was synthesized and resolved to its enantiomers using analytic and semipreparative high-pressure liquid chromatography. The absolute configuration of both fractions was established using vibrational circular dichroism. The in vitro monoamine oxidase (MAO) inhibitory profiles were evaluated for the racemate and both enantiomers separately for the two isoforms of the enzyme. The racemic compound and both enantiomers were found to inhibit hMAO-A selectively and competitively. In particular the R enantiomer was detected as an exceptionally potent and a selective MAO-A inhibitor (K-i = 0.85 x 10(-3) +/- 0.05 x 10(-3) mu M and SI: 2.35 x 10(-5)) whereas S was determined as poorer compound than R in terms of K-i and SI (0.184 +/- 0.007 and 0.001). The selectivity of the enantiomers was explained by molecular modeling docking studies based on the PDB enzymatic models of MAO isoforms.Article Citation Count: 1Assessing protein-ligand binding modes with computational tools: the case of PDE4B(Springer, 2017) Çifii, Gülşah; Aviyente, Viktorya; Akten, Ebru Demet; Monard, GeraldIn a first step in the discovery of novel potent inhibitor structures for the PDE4B family with limited side effects we present a protocol to rank newly designed molecules through the estimation of their IC values. Our protocol is based on reproducing the linear relationship between the logarithm of experimental IC values [(IC)] and their calculated binding free energies (). From 13 known PDE4B inhibitors we show here that (1) binding free energies obtained after a docking process by AutoDock are not accurate enough to reproduce this linear relationshipArticle Citation Count: 12Blind Dockings of Benzothiazoles to Multiple Receptor Conformations of Triosephosphate Isomerase from Trypanosoma cruzi and Human(Wiley-VCH Verlag GmbH, 2011) Kurkcuoglu, Zeynep; Ural, Gulgun; Akten, Ebru Demet; Doruker, PemraWe aim to uncover the binding modes of benzothiazoles which have been reported as specific inhibitors of triosephosphate isomerase from the parasite Trypanosoma cruzi (TcTIM) by performing blind dockings on both TcTIM and human TIM (hTIM). Detailed analysis of binding sites and specific interactions are carried out based on ensemble dockings to multiple receptor conformers obtained from molecular dynamics simulations. In TcTIM dimer dockings the inhibitors preferentially bind to the tunnel-shaped cavity formed at the interface of the subunits whereas non-inhibitors mostly choose other sites. In contrast TcTIM monomer binding interface and hTIM dimer interface do not present a specific binding site for the inhibitors. These findings point to the importance of the tunnel and of the dimeric form for inhibition of TcTIM. Specific interactions of the inhibitors and their sulfonate-free derivatives with the receptor residues indicate the significance of sulfonate group for binding affinity and positioning on the TcTIM dimer interface. One of the inhibitors also binds to the active site which may explain its relatively higher inhibition effect on hTIM.Article Citation Count: 5Calculating Level Densities of Heavy Nuclei by the Shell Model Monte Carlo Method(Academic Press Inc Elsevier Science, 2014) Alhassid, Yoram; Özen, Cem; Nakada, HitoshiThe microscopic calculation of nuclear level densities in the presence of correlations is a difficult many-body problem. The shell model Monte Carlo method provides a powerful technique to carry out such calculations using the framework of the configuration-interaction shell model in spaces that are many orders of magnitude larger than spaces that can be treated by conventional methods. We present recent applications of the method to the calculation of level densities and their collective enhancement factors in heavy nuclei. The calculated level densities are in close agreement with experimental data.Article Citation Count: 18Carboxylic acid derivatives display potential selectivity for human histone deacetylase 6: Structure-based virtual screening molecular docking and dynamics simulation studies(Elsevier Science, 2018) Yelekçi, Kemal; Yelekçi, KemalHuman histone deacetylase 6 (HDAC6) has been shown to play a major role in oncogenic cell transformation via deacetylation of alpha-tubulin making it a viable target of anticancer drug design and development. The crystal structure of HDAC6 catalytic domain 2 has been recently made available providing avenues for structure-based drug design campaign. Here in our continuous effort to identify potentially selective HDAC6 inhibitors structure-based virtual screening of similar to 72 461 compounds was carried out using Autodock Vina. The top 100 compounds with calculated Delta G < -10 kcal/mol were manually inspected for binding mode orientation. Furthermore the top 20 compounds with reasonable binding modes were evaluated for selectivity by further docking against HDAC6 and HDAC7 using Autodock4. Four compounds with a carboxylic fragment displayed potential selectivity for HDAC6 over HDAC7 and were found to have good druglike and ADMET properties. Their docking complexes were then submitted to 10 ns-molecular dynamics (MD) simulation using nanoscale MD (NAMD) software to examine the stability of ligand binding modes. These predicted inhibitors remained bound to HDAC6 in the presence of water and ions and the root-mean-square deviation (RMSD) radius of gyration (Rg) and nonbond distance (protein-ligand) profiles suggested that they might be stable over time of the simulation. This study may provide scaffolds for further lead optimization towards the design of HDAC6 inhibitors with improved selectivity. (C) 2018 Elsevier Ltd. All rights reserved.Article Citation Count: 2Characterization of MWCNT-TiO2 Qps and TiO2 QDs in self-assembled films(Elsevier, 2017) Akkaya Arier, Ümit Özlem; Uysal, Bengü ÖzuğurIn this study the solution which includes TiO2 quantum dots (QDs) was mixed with the multi-wall carbon nanotubes (MWCNTs) to prepare MWCNT-TiO2 QDs composite films. The effect of microstructures on the structural and optical properties of MWCNT-TiO2 QDs composite films was evaluated. The activation energy for crystallite growth of TiO2 QDs which are produced in brookite phases was calculated as 20.3 kJ/mol. The properties of MWCNT-TiO2 QDs composite films were characterized by X-ray diffraction (XRD) scanning electron microscopy (SEM) atomic force microscopy (AFM) and ultraviolet-visible absorption spectroscopy (UV-vis). (C) 2017 Elsevier GmbH. All rights reserved.Article Citation Count: 0Comparison of cation effects on phase transitions of kappa and iota carrageenan(European Polymer Federation, 2010) Tari, Özlem; Pekcan, ÖnderPhase transitions of kappa and iota carrageenan in KCl NaCl and CaCl2 solutions were separately studied during heating and cooling processes by using fluorescence technique. Scattered light I-SC and fluorescence intensity I was monitored against temperature to determine the critical transition temperatures and exponents. Kappa and iota carrageenans with monovalent (KCl NaCl) salt system presented only coil to double helix (c-h) and double helix to coil (h-c) transitions upon cooling and heating processes respectively. Two transition regions were observed in both heating and cooling of the iota carrageenan in CaCl2 solution while in kappa carrageenan only (c-h) and (h-c) transitions was detected. During heating dimers decompose into double helices by making (d-h) transition. At the high temperature region (h-c) transition takes place. During cooling back transitions repeat themselves. A hysteresis was observed between (h-c) and (c-h) for the kappa and iota carrageenan salt system (except CaCl2) respectively. Dimer to double helix (d-h) and double helix to dimer (h-d) transitions were observed for iota carrageenan in CaCl2 salt. The gel fraction exponent beta was measured and found to be in accord with the classical Flory-Stockmayer Model for both kappa and iota carrageenan salt systems.Article Citation Count: 6A comparison of fluorescence and UV-visible spectrometry techniques for thermal phase transitions of agarose gels(Springer, 2015) Arda, Ertan; Kara, Selim; Mergen, Ömer Bahadır; Pekcan, ÖnderIn this study thermoreversible phase transitions of high (HMP) and low (LMP) melting point agarose gels were investigated by using the UV-vis and fluorescence spectroscopy techniques. Pyranine was added to the aqueous solution of agarose as a fluorescence-probe. Transmitted light (I (tr)) and fluorescence emission (I (fl)) intensities from the gel samples with different agarose concentrations were monitored during the heating (gel-sol) and cooling (sol-gel) processes. For the both techniques gel-sol (T (gs)) and sol-gel (T (sg)) transition temperatures were determined from the first derivatives of the sigmoidal transition paths. It was observed that the critical transition temperatures obtained from UV-vis and fluorescence data slightly increased depending on the agarose type and concentration and those values were found to be in accord with each other. Transition activation energies were determined using the Arrhenius type equation and were found to be strongly correlated with the agarose content in the gel system. The produced gel-sol (Delta E (gs)) and sol-gel (Delta E (sg)) transition energies from the fluorescence data were found to be lower than that of the UV-vis data which was attributed to the temperature-dependent fluorescence quenching effect.Article Citation Count: 7Controlling the growth of particle size and size distribution of silica nanoparticles by the thin film structure(Springer, 2012) Uysal, Bengü Özuğur; Tepehan, Fatma ZehraNanostructured silicondioxide thin films were prepared by sol-gel spin coating technique. The SiO2 films were made using a conventional mixture of tetraethoxysilane (TEOS) deionized water and ethanol with various NH3/TEOS ratios. The nanostructured silica films were made using a mixture of the SiO2 sol and regular SiO2 sol to control the enlargement of the particles inside the films. The structural morphological and optical characterizations of the as-deposited and annealed films were carried out using X-ray diffraction (XRD) atomic force microscopy scanning electron microscopy NKD spectrophotometer and ultraviolet-visible (UV-vis) spectroscopy. The transmittance data of the infrared spectra of the films were recorded using an FT-IR Spectrometer. The XRD studies showed that as-deposited films were amorphous and the formation of the alfa-cristobalite phase of the silica film was investigated at annealing temperature close to 1100 A degrees C. Optical properties of the transmittance spectra in the s and p-polarization modes were collected. Refractive indices and extinction coefficients were determined with respect to the NH3/TEOS ratios in the compositions of the films. Optical cut-off wavelength values were investigated from the extrapolation of the absorbance spectra which was estimated from the UV-vis spectroscopy measurements. A red shift in the absorption threshold indicated that the size of silica nanoparticles was increased by an increase in the NH3/TEOS volume ratio from 1:64 to 1:8.Article Citation Count: 22Critical Exponents of Gelation and Conductivity in Polyacrylamide Gels Doped by Multiwalled Carbon Nanotubes(Taylor & Francis Ltd, 2010) Aktas, Demet Kaya; Evingür, Gülşen Akin; Pekcan, ÖnderPolyacrylamide (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 2010Article Citation Count: 4Diffusion energies of oxygen diffusing into polystyrene (PS)/poly (N-isopropylacrylamide) composites(Wiley-Blackwell, 2012) Yargı, Önder; Ugur, Saziye; Pekcan, ÖnderDiffusion coefficient of oxygen penetrating into polystyrene (PS) latex/poly (N-isopropylacrylamide) (PNIPAM) microgel composite films were measured using Fluorescence technique. Three different (5 15 and 40wt%) PS content films were prepared from PS/PNIPAM mixtures. Diffusivity of PS/PNIPAM composite films were studied by diffusion measurements which were performed over the temperature range of 24-70 degrees C. Pyrene was used as the fluorescent probe. The diffusion coefficients (D) of oxygen were determined using the SternVolmer fluorescence quenching method combined with Fickian transport and were computed as a function of temperature for each PS content film. The results showed that D values were strongly dependent on both temperature and PS content in the film. Diffusion energies were measured and found to be dependent on the composition of the composite films. Copyright (C) 2011 John Wiley & Sons Ltd.Article Citation Count: 5Discovery of high affinity ligands for beta(2)-adrenergic receptor through pharmacophore-based high-throughput virtual screening and docking(Elsevier Science Inc, 2014) Yakar, Rüya; Akten, Ebru DemetNovel high affinity compounds for human beta(2)-adrenergic receptor (beta(2)-AR) were searched among the clean drug-like subset of ZINC database consisting of 9928465 molecules that satisfy the Lipinski's rule of five. The screening protocol consisted of a high-throughput pharmacophore screening followed by an extensive amount of docking and rescoring. The pharmacophore model was composed of key features shared by all five inactive states of beta(2)-AR in complex with inverse agonists and antagonists. To test the discriminatory power of the pharmacophore model a small-scale screening was initially performed on a database consisting of 117 compounds of which 53 antagonists were taken as active inhibitors and 64 agonists as inactive inhibitors. Accordingly 7.3% of the ZINC database subset (729413 compounds) satisfied the pharmacophore requirements along with 44 antagonists and 17 agonists. Afterwards all these hit compounds were docked to the inactive apo form of the receptor using various docking and scoring protocols. Following each docking experiment the best pose was further evaluated based on the existence of key residues for antagonist binding in its vicinity. After final evaluations based on the human intestinal absorption (HIA) and the blood brain barrier (BBB) penetration properties 62 hit compounds have been clustered based on their structural similarity and as a result four scaffolds were revealed. Two of these scaffolds were also observed in three high affinity compounds with experimentally known K-i values. Moreover novel chemical compounds with distinct structures have been determined as potential beta(2)-AR drug candidates. (C) 2014 Elsevier Inc. All rights reserved.Article Citation Count: 56Docking studies on monoamine oxidase-B inhibitors: Estimation of inhibition constants (K-i) of a series of experimentally tested compounds(Pergamon-Elsevier Science Ltd, 2005) Yelekçi, Kemal; Yelekçi, KemalMonoamine oxidase (EC1.4.3.4Article Citation Count: 39A 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, PemraAnisotropic 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.Conference Object Citation Count: 0Docking-based virtual screening for potential activity against bacterial pyruvate kinase(Springer, 2017) Ergün, Çağla; Akten, Ebru Demet; Doruker, Pemra[Abstract Not Available]Review Citation Count: 51Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies(Frontiers Media Sa, 2016) Yelekçi, Kemal; Mavridis, Lazaros; Djikic, Teodora; Vucicevic, Jelica; Agbaba, Danica; Yelekçi, Kemal; Mitchell, John B. O.The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer's disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug discovery programs. A probabilistic method, the ParzenRosenblatt Window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands targeting AChE/MAO-A/MAO-B and also D-1-R/D-2-R/5-HT2A-R/H-3-R are promising novel drug candidates with improved efficacy and beneficial neuroleptic and procognitive activities in treatment of Alzheimer's and related neurodegenerative diseases. Structural information for drug targets permits docking and virtual screening and exploration of the molecular determinants of binding, hence facilitating the design of multi-targeted drugs. The crystal structures and models of enzymes of the monoaminergic and cholinergic systems have been used to investigate the structural origins of target selectivity and to identify molecular determinants, in order to design MTDLs.Article Citation Count: 223Drug repurposing for coronavirus (COVID-19): in silico screening of known drugs against coronavirus 3CL hydrolase and protease enzymes(TAYLOR & FRANCIS LTD, 2020) Yelekçi, Kemal; Al-Obaidi, Anas; Sahin, Alp Tegin; Yelekçi, KemalIn 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 KeywordsArticle Citation Count: 10Effect of multiwalled carbon nanotube (MWNT) on the behavior of swelling of polyacrylamide-MWNT composites(Sage Publications Ltd, 2014) Evingür, Gülşen Akin; Pekcan, ÖnderThe 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.Article Citation Count: 4Effects of Precursor Parameters on the Optical and Electrical Properties of AZO Nano-Composite Films(Elsevier GMBH Urban & Fischer Verlag, 2016) Akkaya Arier, Ümit Özlem; Uysal, Bengü ÖzuğurAl doped ZnO (AZO) nano-composite films were synthesized on glass substrates with the sol gel spin coating method at the room temperature. The activation energy of AZO nano-composite films was calculated to be 49 kj/mol for the particles growth. The electrical structural and optical properties of AZO films were determined by changing ZnO:water and ZnO:Al ratios. ZnO:water and ZnO:Al ratios play an important role in controlling the electrical conductivity of the AZO nano-composite films. The optimum doping ratio of Al was found to be 2% in terms of the lowest resistivity and above 2% Al-doping concentration the surface resistivity of AZO nano-composite films starts to increase. The optical highest transmittance of the films of 86% in visible region and low surface resistivity of 70 Omega/square can be obtained for the optimum doping ratio of Al. (C) 2016 Elsevier GmbH. All rights reserved.Article Citation Count: 1Energy needs for drying of PAAm- kappa C composites prepared with various kappa C contents(European Polymer Federation, 2011) Pekcan, Önder; Evingür, Gülşen AkınVarious polyacrylamide (PAAm) - Kappa Carrageenan (kappa C) composite gels were prepared from acrylamide (AAm) N N'- methylenebisacrylamide (BIS) and different kappa C contents by free radical crosslinking copolymerization in water. Pyranine (P) was introduced as a fluorescence probe and scattered light I-sc and fluorescence intensities I from these gels were monitored during drying at different temperature. The fluorescence intensity of pyranine increased as drying time is increased for all samples. The behavior of I was quantified using the Stern-Volmer equation with moving boundary diffusion model. Desorption coefficient D increased as temperature was increased for a given kappa C content. Supporting gravimetrical and volumetric experiments were also carried out during drying of PAAm-kappa C composite gels. The energy Delta E values were measured for the drying processes for each kappa C content gel by using fluorescence gravimetrical and volumetric methods respectively. It is understood that Delta E values increase by increasing kappa C content indicating that energy needs for the drying of high kappa C content gel is larger than low kappa C content gel.
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