Biyoinformatik ve Genetik Bölümü Koleksiyonu

Permanent URI for this collectionhttps://gcris.khas.edu.tr/handle/20.500.12469/46

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Citation Count: 7
Antifungal Screening and in Silico Mechanistic Studies of an In-House Azole Library
(2019) Sarı, Suat; Kart, Didem; Sabuncuoğlu, Suna; Doğan, İnci Selin; Özdemir, Zeynep; Bozbey, İrem; Gencel, Melis; Eşsiz, Şebnem; Reynisson, Jóhannes; Karakurt, Arzu; Saraç, Selma; Dalkara, Sevim
Systemic Candida infections pose a serious public health problem with high morbidity and mortality. C. albicans is the major pathogen identified in candidiasis; however, non-albicans Candida spp. with antifungal resistance are now more prevalent. Azoles are first-choice antifungal drugs for candidiasis; however, they are ineffective for certain infections caused by the resistant strains. Azoles block ergosterol synthesis by inhibiting fungal CYP51, which leads to disruption of fungal membrane permeability. In this study, we screened for antifungal activity of an in-house azole library of 65 compounds to identify hit matter followed by a molecular modeling study for their CYP51 inhibition mechanism. Antifungal susceptibility tests against standard Candida spp. including C. albicans revealed derivatives 12 and 13 as highly active. Furthermore, they showed potent antibiofilm activity as well as neglectable cytotoxicity in a mouse fibroblast assay. According to molecular docking studies, 12 and 13 have the necessary binding characteristics for effective inhibition of CYP51. Finally, molecular dynamics simulations of the C. albicans CYP51 (CACYP51) homology model's catalytic site complexed with 13 were stable demonstrating excellent binding.
Citation Count: 14
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 Count: 5
Distinctive Communication Networks in Inactive States of Beta(2)-Adrenergic Receptor: Mutual Information and Entropy Transfer Analysis
(Wiley, 2020) Soğünmez, Nuray; Akten, Ebru Demet
Mutual information and entropy transfer analysis employed on two inactive states of human beta-2 adrenergic receptor (beta(2)-AR) unraveled distinct communication pathways. Previously, a so-called "highly" inactive state of the receptor was observed during 1.5 microsecond long molecular dynamics simulation where the largest intracellular loop (ICL3) was swiftly packed onto the G-protein binding cavity, becoming entirely inaccessible. Mutual information quantifying the degree of correspondence between backbone-C(alpha)fluctuations was mostly shared between intra- and extra-cellular loop regions in the original inactive state, but shifted to entirely different regions in this latest inactive state. Interestingly, the largest amount of mutual information was always shared among the mobile regions. Irrespective of the conformational state, polar residues always contributed more to mutual information than hydrophobic residues, and also the number of polar-polar residue pairs shared the highest degree of mutual information compared to those incorporating hydrophobic residues. Entropy transfer, quantifying the correspondence between backbone-C(alpha)fluctuations at different timesteps, revealed a distinctive pathway directed from the extracellular site toward intracellular portions in this recently exposed inactive state for which the direction of information flow was the reverse of that observed in the original inactive state where the mobile ICL3 and its intracellular surroundings drove the future fluctuations of extracellular regions.
Citation Count: 1
Effect of Temperature and Graphene Oxide on the Swelling of Paam-Go Composite Gels
(Avestia Publishing, 2019) Osma, Büşra; Akın Evingür, Gülşen; Pekcan, Önder
Graphene 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.
Citation Count: 32
Effects of Gnp Addition on Optical Properties and Band Gap Energies of Pmma Films
(Wiley, 2019) Mergen, Ömer Bahadır; Arda, Ertan; Kara, Selim; Pekcan, Önder
In this study the effects of graphene nanoplatelet (GNP) doping on the optical parameters (absorption coefficient alpha and extinction coefficient k) and the optical transition energies (optical band gap and Urbach energies) of poly(methyl methacrylate)/graphene nanoplatelet (PMMA/GNP) composite films were studied. PMMA/GNP composite films with various GNP mass fractions were prepared by spin coating technique. The absorbance (A) changes of the prepared composites were measured by using UV-Vis technique. The alpha and k values of the composites were obtained from UV-Vis data. The observed rapid increase in A values in UV-region were associated with the optical transitions of GNP electrons from valence to conduction band. The direct (E-d) and indirect (E-i) optical band gap energies of the composites were determined by using Tauc method. Both of the band gap energies were decreased when the GNP content in the PMMA matrix is increased. The decrease in the band gap energies was interpreted as evidence of increased conductivity of the composites. Additionally energies of the band tails (Urbach energy) were calculated. It was seen that the Urbach energy levels were increased with GNP content. POLYM. COMPOS. 40:1862-1869 2019. (c) 2018 Society of Plastics Engineers
Citation Count: 1
Evaluation of the Fractal Dimension of Polyacrylamide During Gelation and Swelling
(Elsevier, 2021) Arda, Ertan; Kara, Selim; Pekcan, Önder; Gülşen, Akın-Evingür
[Abstract Not Available]
Citation Count: 2
Fluorescence and Photon Transmission Techniques for Studying Film Formation From Ps/Go Nanocomposites
(SPRINGER, 2020) M. Selin, Sunay; Şaziye, Uğur; Pekcan, Önder
Steady-state fluorescence and UV-Vis techniques were used to study the film formation behavior of composites consisting of pyrene (P)-labeled polystyrene (PS) latex and graphene oxide (GO) in terms of PS latex/GO volume fraction. PS/GO composite films were prepared on glass substrates with different volume fractions of PS and GO using the drop casting method at room temperature. The film formation behavior of these composites was studied by annealing them at a temperature range of 100-300 degrees C and monitoring the scattered light intensity (I-sc), fluorescence intensity (I-P) from P and transmitted light intensity (I-tr) through the films after each annealing step. The optical results indicate that PS/GO composites showed complete film formation independent of GO volume fraction. The morphological changes in the films were also found to be in consistent with these results.
Citation Count: 3
Fractal Dimension and Phase Transition of Graphene Oxide (go) Doped Polyacrylamide
(ELSEVIER SCI LTD, 2020) Evingür, Gülşen Akın; Pekcan, Önder
Graphene Oxide (GO)- Polyacrylamide composites prepared between 5 and 50 mu l GO were performed by Fluorescence Spectroscopy. The phase transition performed on the composites was measured by calculating the critical exponents, beta and gamma, respectively. In addition, fractal analysis of the composites was calculated by a fluorescence intensity of 427 nm. The geometrical distribution of GO in the composites was calculated based on the power law exponent values using scaling models. While the gelation proceeded GO plates first organized themselves into a 3D percolation cluster with the fractal dimension (D-f) of the composite, D-f = 2.63, then After it goes to diffusion limited clusters with D-f = 1.4, its dimension lines up to a Von Koch curve with a random interval of D-f = 1.14.
Citation Count: 9
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
Citation Count: 25
Homology Modeling of Human Histone Deacetylase 10 and Design of Potential Selective Inhibitors
(Taylor & Francis Inc, 2019) Uba, Abdullahi Ibrahim; Yelekçi, Kemal
Histone 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. Sarma
Citation Count: 14
Identification of Potential Inhibitors of Human Methionine Aminopeptidase (type Ii) for Cancer Therapy: Structure-Based Virtual Screening, Admet Prediction and Molecular Dynamics Studies
(Elsevier, 2020) Weako, Jackson; Uba, Abdullahi Ibrahim; Keskin, Özlem; Gürsoy, Attila; Yelekçi, Kemal
Methionine Aminopeptidases MetAPs are divalent-cofactor dependent enzymes that are responsible for the cleavage of the initiator Methionine from the nascent polypeptides. MetAPs are classified into two isoforms: namely, MetAP1 and MetAP2. Several studies have revealed that MetAP2 is upregulated in various cancers, and its inhibition has shown to suppress abnormal or excessive blood vessel formation and tumor growth in model organisms. Clinical studies show that the natural product fumagillin, and its analogs are potential inhibitors of MetAP2. However, due to their poor pharmacokinetic properties and neurotoxicities in clinical studies, their further developments have received a great setback. Here, we apply structure-based virtual screening and molecular dynamics methods to identify a new class of potential inhibitors for MetAP2. We screened Otava's Chemical Library, which consists of about 3 200 000 tangible-chemical compounds, and meticulously selected the top 10 of these compounds based on their inhibitory potentials against MetAP2. The top hit compounds subjected to ADMET predictor using 3 independent ADMET prediction programs, were found to be drug-like. To examine the stability of ligand binding mode, and efficacy, the unbound form of MetAP2, its complexes with fumagillin, spiroepoxytriazole, and the best promising compounds compound-3369841 and compound-3368818 were submitted to 100 ns molecular dynamics simulation. Like fumagillin, spiroepoxytriazole, and both compound-3369841 and compound-3368818 showed stable binding mode over time during the simulations. Taken together, these uninherited-fumagillin compounds may serve as new class of inhibitors or provide scaffolds for further optimization towards the design of more potent MetAP2 inhibitors -development of such inhibitors would be essential strategy against various cancer types.
Citation Count: 2
Intrinsic Dynamics and Causality in Correlated Motions Unraveled in Two Distinct Inactive States of Human Beta(2)-Adrenergic Receptor
(Amer Chemical Soc, 2019) Söğünmez, Nuray; Akten, Ebru Demet
The alternative inactive state of the human beta(2)-adrenergic receptor originally exposed in molecular dynamics simulations was investigated using various analysis tools to evaluate causality between correlated residue-pair fluctuations and suggest allosteric communication pathways. A major conformational shift observed in the third intracellular loop (ICL3) displayed a novel inactive state featuring an inaccessible G protein binding site blocked by ICL3 and an expanded orthosteric ligand binding site. Residue-based mean square fluctuation and stiffness calculations revealed a significant mobility decrease in ICL3 which induced a mobility increase in the remaining loop regions. This indicates conformational entropy loss in one mobile region being compensated by residual intermolecular motions in other mobile regions. Moreover the extent motions decreased and correlations that once existed between transmembrane helices shifted toward regions with increased mobility. Conditional time-delayed cross-correlation analysis identified distinct driver follower relationship profiles. Prior to its packing freely moving ICL3 was markedly driven by transmembrane helix-8 whereas once packed ICL3 controlled future fluctuations of nearby helices. Moreover two transmembrane helices (H5 and H6) started to control future fluctuations of a remote site the extracellular loop ECL2. This clearly suggests that allosteric coupling between extra- and intracellular parts intensified in agreement with the receptor's well recognized feature which is the inverse proportionality between activity and the degree of coupling.
Citation Count: 0
A 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]
Citation Count: 0
A 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]
Citation Count: 79
Post-Synthetically Elaborated Bodipy-Based Porous Organic Polymers (pops) for the Photochemical Detoxification of a Sulfur Mustard Simulant
(American Chemical Society, 2020) Çetin, M. Mustafa; Atılgan, Ahmet; Beldjoudi, Yassine; Liu, Jian; Stern, Charlotte L.; Çetin, Furkan M.; İslamoğlu, Timur; Farha, Omar K.; Deria, Pravas; Stoddart, Frasser J.; Hupp, Joseph T.
Designing new materials for the effective detoxification of chemical warfare agents (CWAs) is of current interest given the recent use of CWAs. Although halogenated borondipyrromethene derivatives (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene or BDP or BODIPY) at the 2 and 6 positions have been extensively explored as efficient photosensitizers for generating singlet oxygen (1 O2) in homogeneous media, their utilization in the design of porous organic polymers (POPs) has remained elusive due to the difficulty of controlling polymerization processes through cross-coupling synthesis pathways. Our approach to overcome these difficulties and prepare halogenated BODIPYbased porous organic polymers (X-BDP-POP where X = Br or I) represents an attractive alternative through post-synthesis modification (PSM) of the parent hydrogenated polymer. Upon synthesis of both the parent polymer, H-BDP-POP, and its post-synthetically modified derivatives, Br-BDP-POP and I-BDP-POP, the BET surface areas of all POPs have been measured and found to be 640, 430, and 400 m2 g-1, respectively. In addition, the insertion of heavy halogen atoms at the 2 and 6 positions of the BODIPY unit leads to the quenching of fluorescence (both polymer and solution-phase monomer forms) and the enhancement of phosphorescence (particularly for the iodo versions of the polymers and monomers), as a result of efficient intersystem crossing. The heterogeneous photocatalytic activities of both the parent POP and its derivatives for the detoxification of the sulfur mustard simulant, 2-chloroethyl ethyl sulfide (CEES), have been examined; the results show a significant enhancement in the generation of singlet oxygen (1 O2). Both the bromination and iodination of H-BDP-POP served to shorten by 5-fold of the time needed for the selective and catalytic photo-oxidation of CEES to 2-chloroethyl ethyl sulfoxide (CEESO).
Citation Count: 5
Synthesis Molecular Modelling and Antibacterial Activity Against Helicobacter Pylori of Novel Diflunisal Derivatives as Urease Enzyme Inhibitors
(Bentham Science Publ Ltd, 2019) Coşkun, Göknil Pelin; Djikic, Teodora; Kalaycı, Sadık; Yelekçi, Kemal; Şahin, Fikrettin; Küçükgüzel, Şükriye Güniz
Background: The main factor for the prolongation of the ulcer treatment in the gastrointestinal system would be Helicobacter pylori infection which can possibly lead to gastrointestinal cancer. Triple therapy is the treatment of choice by today's standards. However observed resistance among the bacterial strains can make the situation even worse. Therefore there is a need to discover new targeted antibacterial therapy in order to make success in the eradication of H. pylori infections. Methods: The targeted therapy rule is to identify the related macromolecules that are responsible for the survival of the bacteria. Thus 2-[(2'4'-difluoro-4-hydroxybiphenyl-3-yl)carbonyl]-N-( substituted)hydrazinocarbothioamide (3-13) and 5-(2'4'-difluoro-4-hydroxybiphenyl-3-yl)-4-( substituted)-24-dihydro-3H-124-triazole-3-thiones (14-17) were synthesized and evaluated for antibacterial activity in vitro against H. pylori. Results: All of the tested compounds showed remarkable antibacterial activity compared to the standard drugs (Ornidazole Metronidazole Nitrimidazin and Clarithromycin). Compounds 4 and 13 showed activity as 2 mu g/ml MIC value. Conclusion: In addition we have investigated binding modes and energy of the compounds 4 and 13 on urease enzyme active by using the molecular docking tools.
Citation Count: 42
Synthesis, Biological Evaluation and Molecular Docking Studies of Bis-Chalcone Derivatives as Xanthine Oxidase Inhibitors and Anticancer Agents
(Elsevier, 2019) Burmaoğlu, Serdar; Özcan, Şeyda; Balcıoğlu, Sevgi; Gencel, Melis; Noma, Samir Abbas Ali; Eşsiz, Şebnem; Ateş, Burhan; Algül, Öztekin
In this study, a series of B-ring fluoro substituted bis-chalcone derivatives were synthesized by Claisen-Schmidt condensation reactions and evaluated for their ability to inhibit xanthine oxidase (XO) and growth inhibitory activity against MCF-7 and Caco-2 human cancer cell lines, in vitro. According to the results obtained, the bis-chalcone with fluoro group at the 2 (4b) or 2,5-position (4g) of B-ring were found to be potent inhibitors of the enzyme with IC50 values in the low micromolar range. The effects of these compounds were about 7 fold higher than allopurinol. The binding modes of the bis-chalcone derivatives in the active site of xanthine oxidase were explained using molecular docking calculations. Also, compound 4g and 4h showed in vitro growth inhibitory activity against a panel of two human cancer cell lines 1.9 and 6.8 μM of IC50 values, respectively.
Citation Count: 2
Tailoring the Electrical and Optical Properties of Carbon Nanotube Reinforced Transparent Tio 2 Composites by Varying Nanotube Concentrations
(World Scientific Publ Co Pte Ltd, 2019) Uysal, Bengü Özuğur; Akkaya Arier, Ümit Özlem; Pekcan, Önder
In the present work multi-walled carbon nanotube (MWCNT)-doped TiO 2 nanocomposite films were synthesized by sol-gel method. The influence of nanotube concentration on the structural electrical and optical properties of the films was investigated. The beneficial effects of the addition of carbon nanotubes into a TiO 2 film and titania-coated MWCNTs have much in common. On the other hand this work contributes to the previous studies in terms of the optical and electrical properties of MWCNT. For this reason MWCNT/rare brookite-phased TiO 2 matrix as simple sol-gel deposited composite films were investigated in our study. The XRD studies showed that the composite film has a brookite crystal structure at the annealing temperature of 450C. According to the surface morphology investigations SEM image of nanocomposite film shows that composite film has a granular and rod-like structure. The absorbance measurements of the films were carried out by the UV-Vis spectrophotometer to investigate transparency and to calculate the bandgap energy of composite films. The surface resistivity of the MWCNT-doped TiO 2 composites decreased from 2.50×1010 to 2.20×109 ohm/sq with increase in MWCNT content. © 2019 World Scientific Publishing Company.

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