Ebru Demet Akdoğan

Akdoğan, Ebru Demet

Name Variants

Akdoğan, E.
Akdoğan, EBRU DEMET
E. D. Akdoğan
A., Ebru Demet
Ebru Demet Akdoğan
Akten E.
Akdoğan,E.D.
AKDOĞAN, EBRU DEMET
Akdogan,Ebru Demet
Akdogan,E.D.
Akdogan, Ebru Demet
Ebru Demet AKDOĞAN
E. Akdoğan
EBRU DEMET AKDOĞAN
Ebru Demet, Akdogan
Akdoğan, Ebru Demet
Akdoğan, E. D.
A.,Ebru Demet
AKDOĞAN, Ebru Demet
Demet Akdoğan, Ebru
Akten, Ebru Demet
Akdoğan, Ebru Demet
Akdoğan, Ebru Demet
Akdoğan, Demet Akten

Job Title

Prof. Dr.

Email Address

demet.akten@khas.edu.tr

ORCID ID

0000-0002-0358-3171

Scopus Author ID

6507297154

Full item page

Scholarly Output

38

Articles

22

Citation Count

41

Supervised Theses

7 Scholarly Output Search Results

Now showing 1 - 10 of 33

Pharmacophore- Based Screening and Docking for the Discovery of Novel Antagonists of Beta-2 Adrenergic Receptor
(Kadir Has Üniversitesi, 2013) Yakar, Rüya; Akdoğan, Ebru Demet
ß2AR which is the member of rhodopsin-like GPCR is the target system for the discovery of novel antagonists using structure-based pharmacophore modeling and docking methods. initially a shared pharmacophore model is obtained using the structure of five known inactive ß2AR complex (PDB ids: 2HR1 3D4S 3NY8 3NY9 and 3NYA). in order to test the discriminatory power of pharmacophore model a small database consisting of 117 known molecules (53 antagonists against 64 agonists) was screened using LigandScout software tool. The screening yielded 44 antagonists (72% true positives) against 17 agonists (18% false positives) which was found satisfactory. Then under the same screening conditions the second database that is the clean drug-like subset of ZiNC database was screened. -- Abstract'tan.
Investigation of Species-Specific Allosteric Binding Sites in Glycolytic Enzymes Via Allosigma and Molecular Dynamics Simulations
(Kadir Has Üniversitesi, 2021) Çelebi, Metehan; Demet Akdoğan, Ebru
In previous studies of our research group, allosteric sites have been proposed to be used as drug targets in species-specific drug design studies for phosphofructokinase (PFK), glyceraldehyde-3 phosphate dehydrogenase (GADPH) and pyruvate kinase (PK) that belong to three species bacteria, parasite, and human and are essential enzymes in the glycolytic pathway. In this thesis, they were further investigated by various tools such as AlloSigMA and MD simulations. In addition to proposed allosteric sites, known allosteric sites reported by experimental studies for S. aureus PFK and PK enzymes were also investigated. In the first part, AlloSigMA was used to perturb the residues at the proposed and/or known allosteric sites in order to evaluate their allosteric capacities and their effects on protein dynamics. Accordingly, a reduced dynamics in the catalytic sites indicating allosteric inhibition was observed for most of the proposed allosteric sites whereas either an opposite or no effect was observed for known allosteric sites. In addition, partial allosteric inhibition was observed for some of the proposed allosteric sites in human species. In the second part of this thesis, Molecular Dynamics simulations of a total of nine runs, each 100 ns long, were performed for S. aureus phosphofructokinase enzyme in apo and constrained states which incorporated bond restraints at the proposed and known allosteric sites. Here, the goal was to investigate the effect of restraints on the protein's global dynamics. RMSD/RMSF, principal component analysis, the change in orthogonal principal axes, and the mean square distance fluctuation between each pair of residues were determined. According to PCA analysis, increase in the correlation of positional fluctuations between each pair of residues in the chains and domains were observed. Based on the mean square distance fluctuation between residue pairs, each dimer started to communicate more within itself when switched to constrained state.
Citation Count: 0
Tunnel-Like Region Observed as a Potential Allosteric Site In Staphylococcus Aureus Glyceraldehyde-3 Dehydrogenase
(Elsevier Science inc, 2024) Guner-Yilmaz, Ozde Zeynep; Kurkcuoglu, Ozge; Akten, Ebru Demet
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyzing the sixth step of glycolysis has been investigated for allosteric features that might be used as potential target for specific inhibition of Staphylococcus aureus (S.aureus). X-ray structure of bacterial enzyme for which a tunnel-like opening passing through the center previously proposed as an allosteric site has been subjected to six independent 500 ns long Molecular Dynamics simulations. Harmonic bond restraints were employed at key residues to underline the allosteric feature of this region. A noticeable reduction was observed in the mobility of NAD+ binding domains when restrictions were applied. Also, a substantial decrease in cross-correlations between distant C alpha fluctuations was detected throughout the structure. Mutual information (MI) analysis revealed a similar decrease in the degree of correspondence in positional fluctuations in all directions everywhere in the receptor. MI between backbone and sidechain torsional variations changed its distribution profile and decreased considerably around the catalytic sites when restraints were employed. Principal component analysis clearly showed that the restrained state sampled a narrower range of conformations than apo state, especially in the first principal mode due to restriction in the conformational flexibility of NAD+ binding domain. Clustering the trajectory based on catalytic site residues displayed a smaller repertoire of conformations for restrained state compared to apo. Representative snapshots subjected to k-shortest pathway analysis revealed the impact of bond restraints on the allosteric communication which displayed distinct optimal and suboptimal pathways for two states, where observed frequencies of critical residues Gln51 and Val283 at the proposed site changed considerably.
Citation Count: 1
Exploring Distinct Binding Site Regions of Beta(2)-Adrenergic Receptor Via Coarse-Grained Molecular Dynamics Simulations
(Scientific Technical Research Council Turkey-Tubitak, 2013) Cakan, Sibel; Akdoğan, Ebru Demet
beta(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.
Citation Count: 0
Investigation of Allosteric Communication Pathways in Human Beta 2-Adrenergic Receptor
(Wiley-Blackwell, 2015) Akdaş, Başak; Kürkçüoğlu, Özge; Doruker, Pemra; Akten, Ebru Demet
[Abstract Not Available]
Citation Count: 16
In Silico Design of Novel and Highly Selective Lysine-Specific Histone Demethylase Inhibitors
(Scientific Technical Research Council Turkey-Tubitak, 2011) Akdoğan, Ebru Demet; Erman, Burak; Yelekçi, Kemal
Histone 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.
Citation Count: 3
Transmembrane Helix 6 Observed at the Interface of Beta(2)ar Homodimers in Blind Docking Studies
(Taylor & Francis Inc, 2015) Koroğlu, Ayça; Akten, Ebru Demet
Peptide- and protein-protein dockings were carried out on beta(2)-adrenergic receptor (beta(2)AR) to confirm the presence of transmembrane helix 6 (TM6) at the interface region between two beta(2)AR monomers thereby its possible role in dimerization as suggested in numerous experimental and computational studies. Initially a portion of TM6 was modeled as a peptide consisting of 23 residues and blindly docked to beta(2)AR monomer using a rigid body approach. Interestingly all highest score conformations preferred to be near TM5 and TM6 regions of the receptor. Furthermore longer peptides generated from a whole TM region were blindly docked to beta(2)AR using the same rigid body approach. This yielded a total of seven docked peptides each derived from one TM helix. Most interestingly for each peptide TM6 was among the most preferred binding site region in the receptor. Besides the peptide dockings two beta(2)AR monomers were blindly docked to each other using a full rigid-body search of docking orientations which yielded a total of 16000 dimer conformations. Each dimer was then filtered according to a fitness value based on the membrane topology. Among 149 complexes that met the topology requirements 102 conformers were composed of two monomers oriented in opposite directions whereas in the remaining 47 the monomers were arranged in parallel. Lastly all 149 conformers were clustered based on a root mean-squared distance value of 6 angstrom. In agreement with the peptide results the clustering yielded the largest population of conformers with the highest Z-score value having TM6 at the interface region.
Exploring Distinct Conformers of B2-Adrenergic Receptor Via Coarse-Grained Molecular Dynamics Simulations
(Kadir Has Üniversitesi, 2012) Çakan, Sibel; Akdoğan, Demet Akten
ß2AR, G protein bağlantılı reseptör ve birçok ilaç için hedef moleküldür. Reseptörünson derece esnek olan yapısı bir çok ligant molekülünü tanıma özelliği sağlar. Sonyıllarda yapılan kristalografik çalışmalar reseptörün aktif ve inaktif yapısını ortayaçıkarmasına rağmen bu çalışmalar reseptörün tüm dinamiğini çözmek için yeterlideğildir. Moleküler dinamik (MD) metodu reseptörün tüm dinamiğini anlamak içinalternatif ve verimli bir yöntemdir. Ancak geleneksel atomistik simülasyonlar birçokbiyolojik olayın gerçekleştiği zaman aralığı olan milisaniye seviyelerine ulaşamaz.Bu nedenle, bu calışmada serbestlik derecesini azaltan kaba taneli modellemekullanıldı. Sistem POPC membran tabakası içine gömülü ß2AR ve sulardanoluşturuldu. CG model kullanılmasının asıl amacı atomistik modellerde mümkünolmayan daha geniş yapısal alanı ortaya çıkarmaktır. Reseptörün bölgesel hareketleriatomistik simülasyonlarla uyum içindedir. CG simülasyondan dört görüntü seçilmişve geri eşleme yöntemi ile atomistik modele çevrilmiştir. Daha sonra herbiri 100 nsuzunluğunda bir MD simülasyonuna tabi tutulmuştur. Enerjik ve yapısal olarak farklıreseptör yapıları ortaya çıkmıştır. CG MD simülasyonunun PCA analizi, ilk beşbirincil bileşenin tüm dinamiğin %50 sini açıklarken, atomistik simülasyonların %85ini açıkladığını göstermiştir. CG ve atomistik öz-vektörlerin maksimum örtüşmedeğeri 0.46 dır. CG modelde atomistik modele göre korelasyonlar daha zayıftır.
Citation Count: 0
Classification of Distinct Conformers of Beta < 2-Adrenergic Receptor (beta 2-Ar) Based on Binding Affinity of Ligands Through Docking Studies
(Amer Chemical Soc, 2016) Akten, Ebru Demet; Dilcan, Gonca
B2AR reseptörü, akciğerlerin rahatlamasında ve kardiyovasküler fizyolojide rol oynamasıyla önemli bir ilaç hedefidir. Bu çalışmada, çeşitli B2AR konformasyonlarını aktif veya inaktif olarak sınıflandırmak amacıyla, aktivitesi bilinen ligantlar seçilerek onların bağlanma şekillerine göre bir sınıflandırma stratejisi oluşturulmuştur. Önceki bir çalışmada gerçekleştirilen, reseptörün inaktif halinin 2.8 μs'lik MD simülasyonunda, ligandın bağlanma bölgesinin farklı konformasyonları elde edilmiştir. Snapshotlar derlenerek bağlanma bölgesindeki beş anahtar rezidünün RMSD değerlerine göre gruplandırılmıştır. Toplamda 13 farklı konformasyon elde edilmiş ve 5 agonist, 4 ters agonist ve 4 antagonist molekülü her bir konformasyona ayrı ayrı ve 7 farklı skor fonksiyonu kullanılarak dock edilmiştir. En iyi yerleşen konformasyonlar bağlanma bölgesindeki anahtar rezidülerle olan yakınlığına göre seçilmiş ve hesaplanmıştır. Anahtar bölgeye yaklaşamayanlar elenmiş, kalanlar ise skor değerlerine göre sıralanmıştır. Bu sınıflandırma, kritik değerlendirme yapabilmek için MD konformasyonlarından önce aktivitesi bilinen aktif/inaktif kristal yapılara uygulanmıştır. Her skor fonksiyonu tarafından seçilen ve ilk 5'te bulunan MD konformasyonları aktif ve inaktif olarak sınıflandırılmıştır. Son olarak, MD konformasyonlarının ayırt ediciliğini analiz edebilmek için, seçilen bu konformasyonlar ile küçük bir dataset kullanılarak sanal tarama yapılmıştır. MD konformasyonlarının inaktif kristal yapıya göre antagonist/ters agonistler için daha seçici olduğu gözlemlenmiştir. Reseptörün alternatif konformasyonlarını üretmek ve onları sınıflandırmak, genellikle tek bir snaphot X-ray örneği ile sınırlandırılmış ilaç tasarımı çalışmalarında önemli rol oynamaktadır.
Citation Count: 15
Identification of Alternative Allosteric Sites in Glycolytic Enzymes for Potential Use as Species-Specific Drug Targets
(Frontiers Media, 2020) Ayyıldız, Merve; Çeliker, Serkan; Özhelvacı, Fatih; Akten, Ebru Demet
Three allosteric glycolytic enzymes, phosphofructokinase, glyceraldehyde-3 phosphate dehydrogenase and pyruvate kinase, associated with bacterial, parasitic and human species, were explored to identify potential allosteric sites that would be used as prime targets for species-specific drug design purposes using a newly developed approach which incorporates solvent mapping, elastic network modeling, sequence and structural alignments. The majority of binding sites detected by solvent mapping overlapped with the interface regions connecting the subunits, thus appeared as promising target sites for allosteric regulation. Each binding site was then evaluated by its ability to alter the global dynamics of the receptor defined by the percentage change in the frequencies of the lowest-frequency modes most significantly and as anticipated, the most effective ones were detected in the vicinity of the well-reported catalytic and allosteric sites. Furthermore, some of our proposed regions intersected with experimentally resolved sites which are known to be critical for activity regulation, which further validated our approach. Despite the high degree of structural conservation encountered between bacterial/parasitic and human glycolytic enzymes, the majority of the newly presented allosteric sites exhibited a low degree of sequence conservation which further increased their likelihood to be used as species-specific target regions for drug design studies.