TR-Dizin İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://gcris.khas.edu.tr/handle/20.500.12469/4467
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Browsing TR-Dizin İndeksli Yayınlar Koleksiyonu by Department "Fakülteler, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümü"
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Article Citation Count: 0"2-pirazolin yapısındaki yeni bir bileşiğin sentezi, moleküler modellemesi ve monoaminoksidaz inhibitörü etkisinin araştırılması"(Türkiye Halk Sağlığı Kurumu, 2018) Yelekçi, Kemal; Uçar, Gülberk; Yelekçi, KemalAmaç: Nöromediatörlerin yıkımından sorumlu olan monoamin oksidaz (MAO) enziminin izoformlarının (MAO-A ve -B) birçok hastalık ile yakından ilişkili olduğu; MAO inhibitörlerinin depresyon, Parkinson ve Alzheimer hastalığı gibi hastalıkların tedavisinde kullanıldığı bilinmektedir. Grubumuzca daha etkin, tersinir ve az yan etkili yeni bir MAO inhibitörü (SH2U bileşiği) sentezlenmiş ve bu bileşiğin insan MAO enzimini (hMAO) inhibe etme yeteneği incelenmiştir. Ayrıca bu yeni bileşiğin hMAO ile etkileşimi, moleküler modelleme çalışmaları ile detaylı bir şekilde araştırılmıştır. Sentezlenen yeni bileşiğin hMAO’yu kuvvetli bir şekilde yarışmalı ve tersinir olarak inhibe ettiği bulunmuştur. Söz konusu bileşiğin Parkinson ve Alzheimer hastalıklarının tedavisinde ümit verici bir ilaç etken maddesi olabileceği düşünülmektedir. Yöntem: 3’,5’-Dikloro-2’-hidroksi asetofenon ile p-tolualdehit’in metanol içinde KOH varlığında reaksiyona girmesiyle 1-(3,5-dikloro-2-hidroksifenil)- 3-p-tolil prop-2-en-1-on (3’,5’-Dikloro-2’-hidroksi-4- metil şalkon) bileşiği sentez edilmiştir. Daha sonra elde edilen bu bileşiğin etanol içerisinde geri çeviren soğutucu altında izonikotinik asit hidrazit ile muamele edilmesiyle [3-(3,5-dikloro-2-hidroksifenil)-5-p-tolil-4,5- dihidropirazol-1-il] (piridin-4-il) metanon bileşiği sentez edilmiştir. Yapısı doğrulanan bu bileşiğin hMAO enzimi ile etkileşimi, ticari tayin kiti kullanılarak fluorometrik bir yöntemle incelenmiştir. Ayrıca, söz konusu yeni bileşik ile hMAO arasındaki etkileşimler, moleküler modelleme çalışmaları ile aydınlatılmıştır. Bulgular: Sentezlenen bileşiğin yapısı, IR, Mass, 1H-NMR ve elemental analiz yöntemleri kullanılarak doğrulanmıştır. Yapısı doğrulanan bu bileşiğin etkin, seçici, tersinir, toksik olmayan bir hMAO-B inhibitörü olduğu ve inhibisyonun yarışmalı olduğu görülmüştür. Moleküler yerleştirme programı kullanılarak bileşiğin hMAO-B enziminin aktif bölgesinde hangi amino asit yan zincirleri ile ne tür girişimleri yaptığı belirlenmiştir. Sonuç: Yeni sentezlenen SH2U bileşiği, hMAO-B enzimini kuvvetle, seçici, yarışmalı ve tersinir olarak inhibe etmiştir. Sentezlediğimiz bileşik, bilinen seçici ama tersinmez MAO-B inhibitörü olan selejilin’den daha etkin ve seçici, tersinir olarak hMAO-B enzimini inhibe etmiştir ve Parkinson ile Alzheimer hastalığı tedavisinde kullanılabilecek bir ilaç etken maddesi olarak ümit vadetmektedir.Article Citation Count: 14Exploration of the binding pocket of histone deacetylases: the design of potent and isoform-selective inhibitors(Tübitak, 2017) Yelekçi, Kemal; Yelekçi, KemalHistone deacetylases (HDACs) are enzymes that act on histone proteins to remove the acetyl group and thereby regulate the chromatin state. HDACs act not only on histone protein but also nonhistone proteins that are key players in cellular processes such as the cell cycle, signal transduction, apoptosis, and more. “Classical” HDACs have been shown to be promising targets for anticancer drug design and development. However, the selectivity of HDAC inhibitors for HDAC isoforms remains the motivation of current research in this field. Here, we explored Class I HDACs and HDAC6 by sequence alignment and structural superimposition, catalytic channel extraction, and identification of critical residues involved in HDAC catalysis. Based on the general pharmacophore features of known HDAC inhibitors, we developed a library of compounds by scaffold hopping on a fragment hit identified via structurebased virtual screening of the molecular fragment library retrieved from the Otava database. Molecular docking assay revealed five of these compounds to have increased potency and selectivity for HDACs 1 and 2. Furthermore, their predicted absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties were consistent with those of drug-like compounds. With further modelingbased and experimental investigations, we believe that these findings may offer additional potential HDAC inhibitors with improved selectivityArticle Citation Count: 1Exploring distinct binding site regions of beta(2)-adrenergic receptor via coarse-grained molecular dynamics simulations(Scientific Technical Research Council Turkey-Tubitak, 2013) Akdoğan, Ebru Demet; Akdoğan, Ebru Demetbeta(2)-Adrenergic receptor (beta(2)AR) is a G protein-coupled receptor that is highly flexible and able to recognize a wide range of ligands through its conformational variations. Active and inactive conformations revealed by recent crystallographic experiments do not provide a complete dynamic picture of the receptor especially in the binding site. In this study molecular dynamics (MD) simulation through a residue-based coarse-grained model is used as an alternative and efficient method to explore a wider conformational search space. The system was composed of beta(2)AR embedded into a 1-palmitoyl-2-oleoyl-phosphatidylcholine membrane bilayer with surrounding water. A total of 6 mu s of simulation at constant NPT was performed for a system of 6868 coarse-grained beads. The system reached equilibrium at around 0.1 mu s. The overall 3-dimensional structure was well preserved throughout the simulation. Local residue-based fluctuations were in good agreement with fully atomistic MD simulations. Four distinct snapshots were selected and reverse-mapped to all-atom representations with around 65000 atoms. Each reverse-mapped system was later subjected to 100 ns of MD simulation for equilibration. Root mean square deviation clustering analysis yielded distinct receptor conformers for the binding site regions which were suggested to be alternative representations of the binding pocket and thus were proposed as plausible targets in docking-based virtual screening experiments for the discovery of novel antagonists.Article Citation Count: 16In silico design of novel and highly selective lysine-specific histone demethylase inhibitors(Scientific Technical Research Council Turkey-Tubitak, 2011) Akdoğan, Ebru Demet; Yelekçi, Kemal; Yelekçi, KemalHistone lysine-specific demethylase (LSD1) is involved in a wide range of epigenetic processes and plays important roles in gene silencing DNA transcription DNA replication DNA repair and heterochromatin formation. Its active site shows a resemblance to those of 2 homologous enzymes monamine oxidase A and B (MAO-A and MAO-B.) In the present work starting from suitable scaffolds and generating thousands of structures from them 10 potential inhibitors were obtained with structural and physicochemical properties selectively suitable for inhibiting LSD1. iLib Diverse software was used to generate the diverse structures and 3 docking tools CDOCKER GOLD and AutoDock were used to find the most probable potential inhibitor based on its binding affinity. The dispositions of the candidate molecules within the organism were checked by ADMET_PSA_2D (polar surface area) versus ADMET_AlogP98 (the logarithm of the partition coefficient between n-octanol and water) and their suitability is discussed. The LSD1 inhibition activities of the candidates were compared with the properties of trans-2-phenylcyclopropylamine (tranylcypromine) and 2-(4-methoxy-phenyl) cyclopropylamine which are the 2 known inhibitors of LSD1.Article Citation Count: 0Network dynamics reconstruction from data(Scıentıfıc Technıcal Research Councıl Turkey-Tubıtak, 2020) Eroğlu, DenizWe consider the problem of recovering the model of a complex network of interacting dynamical units from time series of observations. We focus on typical networks which exhibit heterogeneous degrees, i.e. where the number of connections varies widely across the network, and the coupling strength for a single interaction is small. In these networks, the behavior of each unit varies according to their connectivity. Under these mild assumptions, our method provides an effective network reconstruction of the network dynamics. The method is robust to a certain size of noise and only requires relatively short time series on the state variable of most nodes to determine: how well-connected a particular node is, the distribution of the nodes' degrees in the network, and the underlying dynamics.Article Citation Count: 5Power of inhibition activity screening and 3D molecular modeling approaches in HDAC 8 inhibitor design(Scientific Technical Research Council Turkey-Tubitak, 2011) Yelekçi, Kemal; Tokluman, Tenzile Deniz; Yelekçi, Kemal; Yurter, HayatIn-vitro inhibition activity screening and in-silico 3D molecular modeling approaches are important tools for design and development of specific histone deacetylase (HDAC) inhibitors. The objective of this study was to investigate the consistency between these 2 approaches. The HDAC 8 inhibition activities of 8 randomly selected different carboxylic acid derivatives were screened and in-vitro experimental results were compared with in-silico molecular modeling calculations. This study demonstrated that there is no sole gold standard technique for inhibitor design and it was concluded that a combination of molecular modeling and activity screening assays will ensure more comprehensive and dependable results.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.