Biyoinformatik ve Genetik Bölümü Koleksiyonu

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

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Now showing 1 - 19 of 19

Citation Count: 1
Assessing protein-ligand binding modes with computational tools: the case of PDE4B
(Springer, 2017) Çifii, Gülşah; Aviyente, Viktorya; Akten, Ebru Demet; Monard, Gerald
In 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 relationship
Citation Count: 12
Blind 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, Pemra
We 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.
Citation Count: 3
Coulomb corrections in the lepton-pair production in ultrarelativistic nuclear collisions
(Amer Physical Soc., 2005) Güçlu, Mehmet C.; Kovankaya, G.; Yılmaz, Melek
We solve the perturbative electron-positron pair production exactly by calculating the second-order Feynman diagrams. We compare our result with Born methods that include Coulomb corrections. We find that a small-momentum approximation is not adequate to obtain exact Coulomb corrections and higher-order terms should also be included. We also compare the impact parameter dependence cross sections.
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: 20
The Drosophila fragile X mental retardation protein participates in the piRNA pathway
(Company of Biologists Ltd, 2015) Bozzetti, Maria Pia; Specchia, Valeria; Cattenoz, Pierre B.; Laneve, Pietro; Geusa, Annamaria; Şahin, H. Bahar; Di Tommaso, Silvia D.; Friscini, Antonella; Massari, Serafina; Diebold, Celine; Giangrande, Angela
RNA metabolism controls multiple biological processes and a specific class of small RNAs called piRNAs act as genome guardians by silencing the expression of transposons and repetitive sequences in the gonads. Defects in the piRNA pathway affect genome integrity and fertility. The possible implications in physiopathological mechanisms of human diseases have made the piRNA pathway the object of intense investigation and recent work suggests that there is a role for this pathway in somatic processes including synaptic plasticity. The RNA-binding fragile X mental retardation protein (FMRP also known as FMR1) controls translation and its loss triggers the most frequent syndromic form of mental retardation as well as gonadal defects in humans. Here we demonstrate for the first time that germline as well as somatic expression of Drosophila Fmr1 (denoted dFmr1) the Drosophila ortholog of FMRP are necessary in a pathway mediated by piRNAs. Moreover dFmr1 interacts genetically and biochemically with Aubergine an Argonaute protein and a key player in this pathway. Our data provide novel perspectives for understanding the phenotypes observed in Fragile X patients and support the view that piRNAs might be at work in the nervous system. © 2015.
Citation Count: 11
Evaluation of selective human MAO inhibitory activities of some novel pyrazoline derivatives
(SPRINGER WIEN, 2013) Yelekçi, Kemal; Yabanoglu-Ciftci, Samiye; Ercan, Ayse; Yelekçi, Kemal; Ucar, Gulberk; Gokhan-Kelekçi, Nesrin
A series of 1-[2-((5-methyl/chloro)-2-benzoxazolinone-3-yl)acetyl]-35-diaryl-45-dihydro-1H-pyrazole derivatives were prepared by reacting 2-((5-methyl/chloro)-2-benzoxazolinone-3-yl)acetylhydrazine with appropriate chalcones. The chemical structures of all compounds were confirmed by elemental analyses IR H-1 NMR and ESI-MS. All the compounds were investigated for their ability to selectively inhibit monoamine oxidase (MAO) by in vitro tests. MAO activities of the compounds were compared with moclobemide and selegiline and all the compounds were found to inhibit human MAO-A selectively. The inhibition profile was found to be competitive and reversible for all compounds by in vitro tests. Among the compounds examined compounds 5ae 5af and 5ag were more selective than moclobemide with respect to the K (i) values experimentally found. In addition the compound 5bg showed MAO-A inhibitor activity as well as moclobemide. A series of experimentally tested compounds (5ae-5ch) were docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The AUTODOCK 4.01 program was employed to perform automated molecular docking.
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: 24
How an Inhibitor Bound to Subunit Interface Alters Triosephosphate Isomerase Dynamics
(Cell Press, 2015) Akdoğan, Ebru Demet; Fındık, Doğa; Akdoğan, Ebru Demet; Doruker, Pemra
The tunnel region at triosephosphate isomerase (TIM)'s dimer interface distant from its catalytic site is a target site for certain benzothiazole derivatives that inhibit TIM's catalytic activity in Trypanosoma cruzi the parasite that causes Chagas disease. We performed multiple 100-ns molecular-dynamics (MD) simulations and elastic network modeling (ENM) on both apo and complex structures to shed light on the still unclear inhibitory mechanism of one such inhibitor named bt10. Within the time frame of our MD simulations we observed stabilization of aromatic clusters at the dimer interface and enhancement of intersubunit hydrogen bonds in the presence of bt10 which point to an allosteric effect rather than destabilization of the dimeric structure. The collective dynamics dictated by the topology of TIM is known to facilitate the closure of its catalytic loop over the active site that is critical for substrate entrance and product release. We incorporated the ligand's effect on vibrational dynamics by applying mixed coarse-grained ENM to each one of 54000 MD snapshots. Using this computationally efficient technique we observed altered collective modes and positive shifts in eigenvalues due to the constraining effect of bt10 binding. Accordingly we observed allosteric changes in the catalytic loop's dynamics flexibility and correlations as well as the solvent exposure of catalytic residues. A newly (to our knowledge) introduced technique that performs residue-based ENM scanning of TIM revealed the tunnel region as a key binding site that can alter global dynamics of the enzyme.
Citation Count: 7
In silico identification of novel and selective monoamine oxidase B inhibitors
(SPRINGER WIEN, 2013) Yelekçi, Kemal; Büyüktürk, Bora; Kayrak, Nurdan
Monoamine oxidases (MAO) A and B are flavin adenine dinucleotides containing enzymes bound to the mitochondrial outer membranes of the cells of the brain liver intestine and placenta as well as platelets. Recently selective MAO-B inhibitors have received increasing attention due to their neuroprotective properties and the multiple roles they can play in the therapy of neurodegenerative disorders. This study was based on 10 scaffolds that were selected from more than a million lead compounds in the ZINCv12 lead library for their structural and physicochemical properties which inhibit MAO-B. Utilizing ZINC and Accelrys 3.1 fragment-based libraries which contain about 400 thousand fragments we generated 200 potential candidates. GOLD LibDock and AutoDock 4.02 were used to identify the inhibition constants and their position in the active sites of both MAO isozymes. The dispositions of the candidate molecules within the organism were checked with ADMET PSA 2D (polar surface area) against ADMET AlogP98 (the logarithm of the partition coefficient between n-octanol and water). The MAO-B inhibition activities of the candidates were compared with the properties of rasagiline which is known to be a selective inhibitor of MAO-B.
Citation Count: 13
In situ steady state fluorescence (SSF) technique to study drying of PAAm hydrogels made of various cross-linker contents
(Elsevier Science, 2009) Evingür, Gülşen Akın; Aktas, Demet Kaya; Pekcan, Önder
Drying experiments of polyacrylamide (PAAm) gels were performed using steady-state fluorescence (SSF) spectrometer. Pyranine (P) was introduced as a fluorescence probe and intensity of P from various crosslinker content gel samples was monitored. It was observed that the intensity of P increased during the in situ drying processes. Gravimetrical and volumetric experiments were also performed. An empirical model was derived and introduced to determine the desorption coefficient D of water molecules from the drying PAAm gels. It is observed that D increased as the cross-linker content was increased. (c) 2008 Elsevier B.V. All rights reserved.
Citation Count: 5
Insights into the binding mode of new N-substituted pyrazoline derivatives to MAO-A: docking and quantum chemical calculations
(SPRINGER WIEN, 2013) Yelekçi, Kemal; Turkkan, Seyhan; Yelekçi, Kemal; Gokhan-Kelekçi, Nesrin
The binding modes of four N-substituted pyrazoline derivatives as novel MAO-A inhibitory agents were investigated using docking and quantum chemical molecular modelling tools.
Citation Count: 4
Molecular docking study based on pharmacophore modeling for novel PhosphodiesteraseIV ınhibitors
(Wiley-VCH Verlag GmbH, 2012) Cifci, Gulsah; Aviyente, Viktorya; Akten, Ebru Demet
In this study pharmacophore modelling was carried out for novel PhosphodiesteraseIV (PDEIV) inhibitors. A pharmacophore-based virtual screening which resulted in 1959 hit compounds was performed with six chemical databases. The pharmacophore screening was proven to be successful in discriminating active and inactive inhibitors using a set of compounds with known activity obtained from ChEMBL database. Furthermore the Lipinskis rule of five was applied for physicochemical filtering of the hit molecules and this yielded 1840 compounds. Three docking software tools AutoDock 4.0 AutoDock Vina and Gold v5.1 were used for the docking process. All 1840 compounds and the known selective inhibitor rolipram were docked into the active site of the target protein. A total of 234 compounds with all three scoring values higher than those of rolipram were determined with the three docking tools. The interaction maps of 14 potent inhibitors complexed with PDEIV B and D isoforms have been analyzed and seven key residues (Asn 395 Gln 443 Tyr 233 Ile 410 Phe 446 Asp 392 Thr 407) were found to interact with more than 80?% of the potent inhibitors. For each one of the 234 hit compounds using the bound conformation with the highest AutoDock score the interacting residues were determined. 117 out of 234 compounds are found to interact with at least five of the seven key residues and these were selected for further evaluation. The conformation with the highest AutoDock score for each 117 compounds were rescored using the DSX scoring function. This yielded a total of 101 compounds with better score values than the natural ligand rolipram. For ADME/TOX calculations the FAF-Drugs2 server was used and 32 out of 101 compounds were found to be non-toxic.
Citation Count: 145
Molecular modifications on carboxylic acid derivatives as potent histone deacetylase inhibitors: Activity and docking studies
(Pergamon-Elsevier Science Ltd, 2009) Yelekçi, Kemal; Dayangac-Erden, Didem; Demir, Ayhan S.; Dalkara, Sevim; Yelekçi, Kemal; Erdem-Yurter, Hayat
In the light of known HDAC inhibitors 33 carboxylic acid derivatives were tested to understand the structural requirements for HDAC inhibition activity. Several modifications were applied to develop the structure-activity relationships of carboxylic acid HDAC inhibitors. HDAC inhibition activities were investigated in vitro by using HeLa nuclear extract in a fluorimetric assay. Molecular docking was also carried out for the human HDAC8 enzyme in order to predict inhibition activity and the 3D poses of inhibitor-enzyme complexes. Of these compounds caffeic acid derivatives such as chlorogenic acid and curcumin were found to be highly potent compared to sodium butyrate which is a well-known HDAC inhibitor. (C) 2009 Elsevier Ltd. All rights reserved.
Citation Count: 123
New pyrazoline bearing 4(3H)-quinazolinone inhibitors of monoamine oxidase: Synthesis biological evaluation and structural determinants of MAO-A and MAO-B selectivity
(Pergamon-Elsevier Science Ltd, 2009) Yelekçi, Kemal; Koyunoğlu, Semra; Yabanoğlu-Çiftçi, Samiye; Yelekçi, Kemal; Özgen, Özen; Uçar, Gülberk; Erol, Kevser; Kendi, Engin; Yeşilada, Akguel; Yelekçi, Kemal
A new series of pyrazoline derivatives were prepared starting from a quinazolinone ring and evaluated for antidepressant anxiogenic and MAO-A and -B inhibitory activities by in vivo and in vitro tests respectively. Most of the synthesized compounds showed high activity against both the MAO-A (compounds 4a-4h 4j-4n and 5g-5l) and the MAO-B (compounds 4i and 5a-5f) isoforms. However none of the novel compounds showed antidepressant activity except for 4b. The reason for such biological properties was investigated by computational methods using recently published crystallographic models of MAO-A and MAO-B. The differences in the intermolecular hydrophobic and H-bonding of ligands to the active site of each MAO isoform were correlated to their biological data. Compounds 4i 4k 5e 5i and 5l were chosen for their ability to reversibly inhibit MAO-B and MAO-A and the availability of experimental inhibition data. Observation of the docked positions of these ligands revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. Among the pyrazoline derivatives it appears that the binding interactions for this class of compounds are mostly hydrophobic. All have potential edge-to-face hydrophobic interactions with F343 as well as pi-pi stacking with Y398 and other hydrophobic interactions with L171. Strong hydrophobic and H-bonding interactions in the MAO recognition of 4i could be the reason why this compound shows selectivity toward the MAO-B isoform. The very high MAO-B selectivity for 4i can be also explained in terms of the distance between the FAD and the compound which was greater in the complex of MAO-A-4i as compared to the corresponding MAO-B complex. (C) 2008 Elsevier Ltd. All rights reserved.
Citation Count: 0
Prediction of the monomer-monomer ınterface region of the beta 2Ar homo-dimer receptor via docking experiments
(Cell Press, 2012) Koroğlu, Ayça
[Abstract Not Available]
Citation Count: 3
Salt inducible kinases as novel Notch interactors in the developing Drosophilaretina
(Public Library Science, 2020) Şahin, H. Bahar; Sayın, Sercan; Holder, Maxine; Bugra, Kuyaş; Çelik, Arzu
Developmental processes require strict regulation of proliferation, differentiation and patterning for the generation of final organ size. Aberrations in these fundamental events are critically important in tumorigenesis and cancer progression.Salt inducible kinases(Siks) are evolutionarily conserved genes involved in diverse biological processes, including salt sensing, metabolism, muscle, cartilage and bone formation, but their role in development remains largely unknown. Recent findings implicate Siks in mitotic control, and in both tumor suppression and progression. Using a tumor model in theDrosophilaeye, we show that perturbation of Sik function exacerbates tumor-like tissue overgrowth and metastasis. Furthermore, we show that bothDrosophila Sikgenes,Sik2andSik3, function in eye development processes. We propose that an important target of Siks may be the Notch signaling pathway, as we demonstrate genetic interaction between Siks and Notch pathway members. Finally, we investigate Sik expression in the developing retina and show that Sik2 is expressed in all photoreceptors, basal to cell junctions, while Sik3 appears to be expressed specifically in R3/R4 cells in the developing eye. Combined, our data suggest thatSikgenes are important for eye tissue specification and growth, and that their dysregulation may contribute to tumor formation.
Citation Count: 33
Synthesis and molecular modeling of some novel hexahydroindazole derivatives as potent monoamine oxidase inhibitors
(Pergamon-Elsevier Science Ltd, 2009) Yelekçi, Kemal; Şimşek, O. Özgün; Ercan, Ayşe; Yelekçi, Kemal; Şahin, Z. Sibel; Işık, Şamil; Uçar, Gülberk; Bilgin, Abdullah Altan
A novel series of 2-thiocarbamoyl-234567-hexahydro-1H-indazole and 2-substituted thiocarbamoyl-33a 4567-hexahydro-2H-indazoles derivatives were synthesized and investigated for the ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). The target molecules were identified on the basis of satisfactory analytical and spectra data (IR H-1 NMR C-13 NMR D-2 NMR DEPT EI-MASS techniques and elemental analysis). Synthesized compounds showed high activity against both the MAO-A (compounds 1d 1e 2c 2d 2e) and the MAO-B (compounds 1a 1b 1c 2a 2b) isoforms. In the discussion of the results the influence of the structure on the biological activity of the prepared compounds was delineated. It was suggested that non-substituted and N-methyl/ethyl bearing compounds (except 2c) increased the inhibitory effect and selectivity toward MAO-B. The rest of the compounds carrying N-allyl and N-phenyl appeared to select the MAO-A isoform. The inhibition pro. le was found to be competitive and reversible for all compounds. A series of experimentally tested (1a-2e) compounds was docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The AUTODOCK 4.01 program was employed to perform automated molecular docking. In order to see the detailed interactions of the docked poses of the model inhibitors compounds 1a 1d 1e and 2e were chosen because of their ability to reversibly inhibit the MAO-B and MAO-A and the availability of experimental inhibition data. The differences in the intermolecular hydrophobic and H-bonding of ligands to the active site of each MAO isoform were correlated to their biological data. Observation of the docked positions of these ligands revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. Excellent to good correlations between the calculated and experimental K-i values were obtained. In the docking of the MAO-A complex the trans configuration of compound 1e made various very close interactions with the residues lining the active site cavity these interactions were much better than those of the other compounds tested in this study. This tight binding observation may be responsible for the nanomolar inhibition of form of MAOA. However it binds slightly weaker (experimental K-i = 1.23 mu M) to MAO-B than to MAO-A (experimental K-i = 4.22 nM). (C) 2009 Elsevier Ltd. All rights reserved.
Citation Count: 14
Synthesis molecular modeling and in vitro screening of monoamine oxidase inhibitory activities of some novel hydrazone derivatives
(SPRINGER WIEN, 2013) Yelekçi, Kemal; Gokhan-Kelekçi, Nesrin; Yabanoglu-Ciftci, Samiye; Yelekçi, Kemal; Ucar, Gulberk
Thirteen 2-[2-(5-methyl-2-benzoxazolinone-3-yl)acetyl]-3/4/5-substituted benzylidenehydrazine derivatives were synthesized by reacting 2-(5-methyl-2-benzoxazolinone-3-yl)acetylhydrazine and substituted benzaldehydes in neutral and acid/base catalyzed conditions and a comparison was made in terms of their yields and reaction times. The structures of all compounds were confirmed by IR H-1 NMR C-13 NMR mass spectral data and elemental analyses. All the compounds were investigated for their ability to selectively inhibit MAO isoforms by in vitro tests and were found to inhibit recombinant human MAO-B selectively and reversibly in a competitive manner. Among the compounds examined compound 16 was found to be more selective than selegiline a known MAO-B inhibitor in respect to the K (i) values experimentally found. Additionally compounds 9 and 15 showed moderate MAO-B inhibitor activity. The interaction of compounds with MAO isoforms was investigated by molecular docking studies using recently published crystallographic models of MAO-A and MAO-B. The results obtained from the docking studies were found to be in good agreement with the experimental values.
Citation Count: 28
A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations
(Public Library Science, 2015) Eşsiz, Şebnem; Eşsiz, Şebnem; Lau, Edmond Y.; Fattebert, Jean-Luc; Emigh, Aiyana; Lightstone, Felice C.
Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone and sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures.

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