Biyoinformatik ve Genetik Bölümü Koleksiyonu
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Article Citation Count: 28Effect of intracellular loop 3 on intrinsic dynamics of human 2-adrenergic receptor(Bmc, 2013) Ozcan, Ozer; Uyar, Arzu; Doruker, Pemra; Akten, Ebru DemetBackground: To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human beta(2)-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 mu s molecular dynamics (MD) simulation at 310 K. Results: After around 600 ns, the loop model started a transition to a very inactive conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein's binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 angstrom from 11 angstrom, which was further elaborated by docking studies. Conclusions: The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the very inactive state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes.Article Citation Count: 9Surfactant-free one-step fabrication of gelatin/PAAm/MWCNT composites for biomedical applications(Springer, 2021) Duzkan, Berke; Uysal, Bengü Özuğur; Pekcan, ÖnderWell-dispersed multiwalled carbon nanotube (MWCNT) and gelatin-enhanced polyacrylamide (PAAm) composites were synthesized via a free-radical copolymerization method. MWCNTs were added to the composite mixture in various amounts (0.5 mg, 1.0 mg, 1.5 mg, and 2.0 mg) during the nucleation process in order to increase the conductivity. Gelatin/PAAm/MWCNT composites containing different amounts of MWCNTs were then characterized using the ultraviolet-visible (UV-vis) spectroscopic technique to illuminate the dispersibility, and optical properties of the composites. Bandgap energies were evaluated by measuring the absorbance spectra of the composites in a quartz cuvette of the UV-vis spectrophotometer. By calculating the resonance ratio and normalized width values from the absorption response of the composites according to the wavelength, the dispersion rate of the MWCNTs in the composite matrix was determined. The proper ultra-sonication process has been realized so as to maintain the good dispersion of the MWCNTs inside the polymeric matrix lowering the normalized width and increasing the resonance ratio. Polymeric composite materials based on carbon nanotubes are of considerable interest for a variety of biomedical applications. Furthermore, in this work, it is argued that the use of gelatin, another biocompatible material, together with MWCNT makes the properties of the formed composite, suitable for the desired biomedical applications.Book Part Citation Count: 2Conductivity Percolation of Carbon Nanotubes in Polyacrylamide Gels(Intech Europe, 2011) Pekcan, Önder; Evingür, Gülşen Akın[Abstract Not Available]Article Citation Count: 8Sorption and Desorption of PVA-Pyrene Chains in and out of Agarose Gel(Springer/Plenum Publishers, 2012) Kara, Selim; Gacal, Burçin; Tunç, Deniz; Yağcı, Yusuf; Pekcan, ÖnderIn situ steady-state fluorescence (SSF) measurement technique was applied to investigation of pyrene labeled Poly(vinyl alcohol) (PVA-Py) molecules diffusion in and out of agarose gels. Gel samples with four different concentration of agarose were prepared. PVA-Py was synthesized by "click" chemistry method and dissolved in water to use in diffusion experiments. The results were analyzed by using Fickian type diffusion model, and it was found that sorption and desorption processes of PVA-Py molecules in and out of agarose gel have two distinct regions for short and long diffusion times. Sorption and desorption coefficients were measured and it was seen that the diffusion rates were much larger at short times and at lower agarose concentrations.Review Citation Count: 14GELATION MECHANISMS(World Scientific Publ Co Pte Ltd, 2012) Pekcan, Önder; Kara, SelimIn this paper, we survey the gelation mechanisms for various polymeric systems which are classified by the type and the strength of the cross-linkages. These are the "irreversible" gels that are cross-linked chemically by covalent bonds and the "reversible" gels that are cross-linked physically by hydrogen or ionic bonds and by the physical entanglement of polymer chains. Some of the natural polymer gels fall into the class of physical gels, among which the red algae that has attracted attention for various applications is discussed in detail. Various composite gels, formed from mixture of physical and chemical gels are also discussed in the last section of the article. Theoretical models describe the gelation as a process of random linking of subunits to larger and larger molecules by formation of an infinite network, where no matter what type of objects are linked, there is always a critical "gel point" at which the system behaves neither as a liquid nor as a solid on any length scale. The Flory-Stockmayer theory and percolation theory provide bases for modeling this sol-gel phase transition. The experimental techniques for measuring the critical exponents for sol-gel phase transitions in different polymeric systems are introduced and the validation of various theoretical predictions are surveyed.Article Citation Count: 1Evaluation of the fractal dimension of polyacrylamide during gelation and swelling(Elsevier, 2021) Arda, Ertan; Kara, Selim; Pekcan, Önder; Gülşen, Akın-Evingür[Abstract Not Available]Conference Object Citation Count: 0Soman as a wrench in the works of human acetylcholinesterase: Soman induced conformational changes revealed by molecular dynamics simulations(Amer Chemical Soc, 2014) Eşsiz, Şebnem; Eşsiz, Şebnem; Lau, Edmond Y.; Fattebert, Jean-Luc; Emigh, Aiyana; Lightstone, Felice C.[Abstract Not Available]Conference Object Citation Count: 3A mathematical characterization of the gel point in sol-gel transition(IOP Publishing Ltd, 2015) Bilge, Ayşe Hümeyra; Pekcan, ÖnderWe model the sol-gel transition in terms of Susceptible-Infected-Removed (SIR) and Susceptible-Exposed-Infected-Removed (SEIR) models and compare with experimental results. We show, numerically, that the "gel point" described as the onset of the gelation phenomena and measured experimentally, corresponds to an accumulation point of the extreme values of the derivatives of the gelation curve. We define the "critical point of a sigmoidal curve" as the limit of the points where the derivatives reach their extreme values, provided that this limit exists.Conference Object Citation Count: 1Effect of temperature and graphene oxide on the swelling of PAAm-GO composite gels(Avestia Publishing, 2019) Osma, Büşra; Akın Evingür, Gülşen; Pekcan, ÖnderGraphene oxide (GO) is a two dimensional carbon material with similar one-atom thickness, and is a light material having extremely high strength and thermal stability [1]. Thus, GO is an efficient filler for the enhancement of the electrical, mechanical and thermal properties of composite materials [2]. We focused on GO as a nanofiller in polyacrylamide hydrogels and PAAm-GO composites to investigate the effect of temperature and graphene oxide on the swelling. Polyacrylamide (PAAm) hydrogels have been proposed for use as promising biomaterials in biomedical and tissue engineering. The composite gels were prepared by free radical crosslinking copolymerization with GO content varying in the range between 8 and 50 μl of GO. The effects of temperature and graphene oxide on the swelling of the composites were studied. The swelling experiment was performed in the distilled water. Decreasing in pyranine (Py) as a fluorescence probe and emission light intensity (Iem) were monitored by steady state fluorescence spectroscopy. Since the increase in Isc corresponds to the increase in turbidity of the swelling composite gel, the corrected fluorescence intensity, I was introduced to analyze the swelling processes. The Stern-Volmer equation combined with Li-Tanaka models was used to explain the behaviour of I during swelling processes. The cooperative diffusion coefficients and time constants were calculated as a function of temperature and GO, respectively.Book Part Citation Count: 0EFFECT OF CONTENT AND TEMPERATURE ON THE PHASE TRANSITIONS OF POLYMER COMPOSITES DOPED BY KAPPA CARRAGEENAN AND ALGINATE(Elsevier Academic Press Inc, 2016) Evingür, Gülşen Akın; Pekcan, Önder[Abstract Not Available]Article Citation Count: 3The modifier effects of chymotrypsin and trypsin enzymes on fluorescence lifetime distribution of "N-(1-pyrenyl)maleimide-bovine serum albumin" complex(Pergamon-Elsevier Science LTD, 2016) Özyiğit, İbrahim Ethem; Karakuş, Emine; Pekcan, ÖnderChymotrypsin and trypsin are the well known proteolytic enzymes, both of which are synthesized in the pancreas as their precursors the inactive forms; chymotrypsinogen and trypsinogen and then are released into the duodenum to cut proteins into smaller peptides. In this paper, the effects of activities of chymotrypsin and trypsin enzymes on fluorescence lifetime distributions of the substrat bovine serum albumin (BSA) modified with N-(1-pyrenyl)maleimide (PM) were examined. In the labeling study of BSA with PM, it is aimed to attach PM to the single free thiol (Cys34) and to all the free amine groups in accessible positions in order to produce excimers of pyrene planes of the possible highest amount to form the lifetime distributions in the widest range, that may show specifically distinguishing changes resulting from the activities of the proteases. The time resolved spectrofluorometer was used to monitor fluorescence decays, which were analyzed by using the exponential series method (ESM) to obtain the changes of lifetime distributions. After the exposure of the synthesized substrat PM-BSA to the enzymes, the fluorescence lifetime distributions exhibited different structures which were attributed to the different activities of the proteases. (C) 2015 Elsevier B.V. All rights reserved.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: 5Design, Synthesis and hMAO Inhibitory Screening of Novel 2-Pyrazoline Analogues(Bentham Science Publ Ltd, 2017) Yelekçi, Kemal; Uçar, Gülberk; Yelekçi, KemalAim 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.Conference Object Citation Count: 0Investigation of intrinsic dynamics and allosteric coupling in human beta 2-adrenergic receptor(Springer, 2017) Özcan, Özer; Özgür, Canan; Doruker, Pemra; Akten, Ebru Demet[Abstract Not Available]Article Citation Count: 16Pharmacophore-based virtual screening for identification of potential selective inhibitors of human histone deacetylase 6(Elsevier Sci Ltd, 2018) Yelekçi, Kemal; Yelekçi, KemalHistone deacetylase (HDAC) 6 plays a role in oncogenic transformation and cancer metastasis via tubulin deacetylation, making it a critical target for anticancer drug design. However, lack of selectivity shown by many of the current HDAC6 inhibitors in clinical use and trials prompts the continuous search for selective inhibitors. Here, 10 pharmacophore hypotheses were developed based on the 3D common features of training set of 20 HDAC inhibitors in clinical use and trials. The hypotheses were validated using a test set of another 20 HDAC inhibitors along with 400 inactive (decoys) molecules based on Giiner-Henry pharmacophore scoring method. Hypothesis 1 consisting of 1 H-bond donor, 1 H-bond acceptor and 2 hydrophobic features, was used to screen "DruglikeDiverse" database using Biovia Discovery Studio 4.5. The top 10 hit compounds were selected based on the pharmacophore fit values ( > 3.00). Their binding affinity against HDAC6 compared to class I HDACs (1, 2, 3 & 8) and a class IIa member (HDAC7), was calculated by molecular docking using AutoDock4. The stability of binding modes of 2 potential HDAC6-selective inhibitors (ENA501965 and IBS399024) was examined by 30 ns-molecular dynamics (MD) simulation using nanoscale MD (NAMD) software. Both ligands showed potential stability in HDAC6 active site over time. Therefore, these may provide additional scaffolds for further optimization towards the design of safe, potent and selective HDAC6 inhibitors.Conference Object Citation Count: 0A new thiadiazine derivative induces oxidative stress dependent JNK pathway activation and cell death in hepatocellular carcinoma(Amer Assoc Cancer Research,, 2019) Kahraman, Deniz Cansen; Bilget Güven, Ebru; Tozkoparan, Birsen; Çetin Atalay, Rengül[Abstract Not Available]Conference Object Citation Count: 0Intermolecular interactions in human HDAC8 crystal structures and the stability of binding modes of co-crystallized inhibitors(Amer Chemical Soc, 2019) Yelekçi, Kemal; Uba, Abdullahi Ibrahim[Abstract Not Available]Article Citation Count: 25Homology modeling of human histone deacetylase 10 and design of potential selective inhibitors(Taylor & Francis Inc, 2019) Yelekçi, Kemal; Yelekçi, KemalHistone deacetylases (HDACs) are implicated in the pathology of various cancers, and their pharmacological blockade has proven to be promising in reversing the malignant phenotypes. However, lack of crystal structures of some of the human HDAC isoforms (e.g., HDAC10) hinders the design of the isoform-selective inhibitor. Here, the recently solved X-ray crystal structure of Danio rerio (zebrafish) HDAC10 (Protein Data Bank (PDB) ID; 5TD7, released on 24 May 2017) was retrieved from the PDB and used as a template structure to model the three-dimensional structure of human HDAC10. The overall quality of the best model (M0017) was assessed by computing its z-score-a measure of the deviation of the total energy of the structure with respect to an energy distribution derived from random conformations and by docking of known HDAC10 inhibitors to its catalytic cavity. Furthermore, to identify potential HDAC10-selective inhibitor ligand-based virtual screening was carried out against the ZINC database. The free modeled structure of HDAC10 and its complexes with quisinostat and the highest-ranked compound ZINC19749069 were submitted to molecular dynamics simulation. The comparative analysis of root-mean-squared deviation, root-mean-squared fluctuation, radius of gyration (Rg), and potential energy of these systems showed that HDAC10-ZINC19749069 complex remained the most stable over time. Thus, M0017 could be potentially used for structure-based inhibitor against HDAC10, and ZINC19749069 may provide a scaffold for further optimization. Communicated by Ramaswamy H. SarmaConference Object Citation Count: 0A NEW THIADIAZINE DERIVATIVE INDUCES OXIDATIVE STRESS DEPENDENT CELL DEATH IN HEPATOCELLULAR CARCINOMA STEM CELLS(Wiley, 2019) Kahraman, Deniz Cansen; Bilget Güven, Ebru; Aytaç, Peri; Tozkoparan, Birsen; Çetin Atalay, Rengül[Abstract Not Available]Article Citation Count: 8Synthesis, in silico studies and cytotoxicity evaluation of novel 1,3,4-oxadiazole derivatives designed as potential mPGES-1 inhibitors(MARMARA UNIV, 2020) Yelekçi, Kemal; Ding, Kai; Zhan, Chang-Guo; Elmezayen, Ammar D.; Yelekçi, Kemal; Duracık, Merve; Özakpınar, Özlem Bingol; Küçükgüzel, İlkayA series of new 1,3,4-oxadizole derivatives containing thioether group, has been synthesized to investigate their mPGES-1 inhibitory activities. The synthesized compounds were also evaluated for their anticancer and COX-1/2 inhibitory activities. All compounds were checked for their purity using TLC and HPLC analyses. The melting points, elemental analysis, FT-IR, H-1-/C-13-NMR and LR-MS data were utilized for structural characterization. The most potent derivative was 2-[5-{[2-methyl-5-(propan-2-yl)phenoxy]methyl}-1,3,4-oxadiazol-2-yl)sulphanyl]-1-(phenyl)ethan-1-one 3a, which showed inhibitory activity against mPGES-1 with an IC50 of 4.95 mu M. Docking studies with mPGES-1 and COX-1/2 enzymes revealed their affinity and potential binding mechanism for the tested compounds.
