Akdoğan, Ebru Demet
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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
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
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Prof. Dr.
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Molecular Biology and Genetics
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Sustainable Development Goals
11
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17
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14
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3
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4
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10
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13
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5
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Documents
23
Citations
217
h-index
8
Documents
37
Citations
658
Scholarly Output
39
Articles
27
Views / Downloads
245/15367
Supervised MSc Theses
8
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0
WoS Citation Count
238
Scopus Citation Count
250
WoS h-index
9
Scopus h-index
9
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0
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0
WoS Citations per Publication
6.10
Scopus Citations per Publication
6.41
Open Access Source
27
Supervised Theses
8
| Journal | Count |
|---|---|
| Journal of Biomolecular Structure and Dynamics | 3 |
| Journal of Computer-Aided Molecular Design | 2 |
| Archives of Biochemistry and Biophysics | 2 |
| Molecular Informatics | 2 |
| Biophysical Journal | 1 |
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39 results
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Now showing 1 - 10 of 39
Article Citation - WoS: 17Citation - Scopus: 20In 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, 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.Master Thesis Hekzokinazda Türe Özgü Allosterik İnhibitörlerin Tasarlanması ve ST2 Reseptörü için İnhibisyon Gücünün Arttırılması İçin Allosterik Alanların Tespiti(2025) Vural, Latife Sude; Akdoğan, Ebru DemetMilyonlarca insanı enfekte eden antimalaryal dirençli parazitlerin neden olduğu hastalıkları tedavi etmek için türlere özgü ilaçların geliştirilmesi literatürde vurgu bulmuştur. Glikolitik yol, hücrenin en temel enerji kaynağı olduğundan, bu yoldaki enzimler potansiyel ilaç hedefleri haline gelmiştir. Ancak, önerilen ilaç adayları insan türünde aynı enzimleri inhibe etmemelidir. Buna göre, allosterik inhibitörler, enfekte eden türe ait enzimlerdeki evrimsel olarak en az korunan alanları hedefledikleri için alternatif hale gelirler. Tezin ilk proteini, Plasmodium vivax heksokinazındaki alternatif potansiyel ve spesifik allosterik bölgelerin tanımlanması ve analiziydi. Bu tezde araştırılan ikinci sistem, enfeksiyon, inflamasyon ve alerji sırasında tip 2 bağışıklık tepkilerinde önemli bir sitokin olan İnterlökin-33'e (IL-33) odaklanmıştır. Amaç, IL-33 ile etkileşimini engellemek ve böylece bağışıklık aktivasyonunu düzenlemek için reseptörü ST2'yi inhibe etmekti. Hesaplamalı yaklaşımımızın ilk adımında, enzimin yüzeyindeki potansiyel bağlanma yerlerini belirlemek için bir dizi etkili araç kullanıldı. Heksokinaz için çeşitli bağlanma yerleri tanındı, bunlardan bazıları alt birimlerin arayüzünde, bazıları ise merkezde yer alıyordu ve bu da onları allosterik düzenleme için kritik sıcak noktalar haline getiriyordu. ST2 için, birden fazla allosterik potansiyel bağlanma yeri bulundu ve bu da inhibisyon potansiyelini artırdı. İkinci aşamada, her bağlanma yerinin allosterik potansiyeli, CorrSite, Ohm, AlloSigma ve ESSA gibi elastik ağ modellemesine dayalı çeşitli hesaplamalı araçlar ve makine öğrenme algoritması PASSER ile değerlendirildi. Heksokinaz için, parazit ve insan arasındaki dizi hizalaması, her potansiyel allosterik yerin özgüllüğünü doğrulamak için benzerlik derecesini belirlemek amacıyla kullanıldı. Son adımda, 1615 FDA onaylı bileşiğin yüksek allosterik potansiyele ve yüksek özgüllük derecesine sahip yerlere yerleştirilmesi, heksokinaz ve ST2 reseptörünün inhibisyonunda etkili olabilecek bazı kritik bileşiklerin elde edilmesini sağladı. Yakın gelecekte bu bileşiklerin deneysel doğrulaması, hesaplamalı yaklaşımımızı desteklemek amacıyla gerçekleştirilecektir.Master Thesis Exploring Distinct Conformers of B2-Adrenergic Receptor Via Coarse-Grained Molecular Dynamics Simulations(Kadir Has Üniversitesi, 2012) Çakan, Sibel; Akdoğan, Demet Aktenß2AR, 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.Article pH-Driven β2AR Dynamics Reveal Loop-Mediated Allosteric Communication(Amer Chemical Soc, 2026) Sogunmez Erdogan, Nuray; Akten, E. DemetMembrane protein structure and dynamics are highly sensitive to environmental conditions, including changes in pH that can alter the protonation states of ionizable residues and, in turn, influence local electrostatics and stability. Constant-pH molecular dynamics (CpHMD) provides a framework to explore such effects by allowing dynamic proton exchange during simulations. Here, we applied CpHMD at pH:6.5, 7.0, and 8.0, alongside conventional MD, to examine how pH variations may influence the local conformational behaviors of the beta 2-adrenergic receptor (beta 2AR). During the 1.2-mu s-long total simulation, loop regions rich in titratable residues, particularly ICL3 and ECL2, showed the strongest responses to protonation changes. CpHMD trajectories suggested a pH-dependent redistribution of loop flexibility and hydrogen-bonding patterns, producing a see-saw-like effect, while fixed-protonation Control runs showed more constrained behavior. Across all simulations, the key GPCR microswitches, such as the ionic lock, the Y-Y gate, the NPxxY and PIF motifs, and the Trp286-Phe290 toggle pair, stayed within the ranges expected for an inactive receptor. This suggests that pH changes mainly influence local loop motions in the inactive receptor without pushing it toward activation-like states. Finally, mutual information analysis on both C alpha atoms and dihedral angles revealed altered communication between the extracellular and intracellular loops under different pH environments. While limited in time scale, these results provide a computational perspective on how protonation dynamics can modulate the GPCR behavior and highlight the value of incorporating pH effects in molecular-level investigations.Article 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, GoncaB2AR 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.Article Citation - WoS: 5Citation - Scopus: 5Discovery of High Affinity Ligands for Beta(2)-Adrenergic Receptor Through Pharmacophore-Based High-Throughput Virtual Screening and Docking(Elsevier Science Inc, 2014) Yakar, Rüya; Akten, Ebru DemetNovel high affinity compounds for human beta(2)-adrenergic receptor (beta(2)-AR) were searched among the clean drug-like subset of ZINC database consisting of 9928465 molecules that satisfy the Lipinski's rule of five. The screening protocol consisted of a high-throughput pharmacophore screening followed by an extensive amount of docking and rescoring. The pharmacophore model was composed of key features shared by all five inactive states of beta(2)-AR in complex with inverse agonists and antagonists. To test the discriminatory power of the pharmacophore model a small-scale screening was initially performed on a database consisting of 117 compounds of which 53 antagonists were taken as active inhibitors and 64 agonists as inactive inhibitors. Accordingly 7.3% of the ZINC database subset (729413 compounds) satisfied the pharmacophore requirements along with 44 antagonists and 17 agonists. Afterwards all these hit compounds were docked to the inactive apo form of the receptor using various docking and scoring protocols. Following each docking experiment the best pose was further evaluated based on the existence of key residues for antagonist binding in its vicinity. After final evaluations based on the human intestinal absorption (HIA) and the blood brain barrier (BBB) penetration properties 62 hit compounds have been clustered based on their structural similarity and as a result four scaffolds were revealed. Two of these scaffolds were also observed in three high affinity compounds with experimentally known K-i values. Moreover novel chemical compounds with distinct structures have been determined as potential beta(2)-AR drug candidates. (C) 2014 Elsevier Inc. All rights reserved.Article Citation - WoS: 5Citation - Scopus: 7Molecular Docking Study Based on Pharmacophore Modeling for Novel Phosphodiesteraseiv Inhibitors(Wiley-VCH Verlag GmbH, 2012) Cifci, Gulsah; Aviyente, Viktorya; Akten, Ebru DemetIn 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.Article Citation - WoS: 4Citation - Scopus: 4Altered Dynamics of S. Aureus Phosphofructokinase Via Bond Restraints at Two Distinct Allosteric Binding Sites(Academic Press Ltd- Elsevier Science Ltd, 2022) Celebi, Metehan; Akten, Ebru DemetThe effect of perturbation at the allosteric site was investigated through several replicas of molecular dynamics (MD) simulations conducted on bacterial phosphofructokinase (SaPFK). In our previous work, an alternative binding site was estimated to be allosteric in addition to the experimentally reported one. To highlight the effect of both allosteric sites on receptor's dynamics, MD runs were carried out on apo forms with and without perturbation. Perturbation was achieved via incorporating multiple bond restraints for residue pairs located at the allosteric site. Restraints applied to the predicted site caused one dimer to stiffen, whereas an increase in mobility was detected in the same dimer when the experimentally resolved site was restrained. Fluctuations in C-alpha-C-alpha distances which is used to disclose residues with high potential of communication indicated a marked increase in signal transmission within each dimer as the receptor switched to a restrained state. Cross-correlation of positional fluctuations indicated an overall decrease in the magnitude of both positive and negative correlations when restraints were employed on the predicted allosteric site whereas an exact opposite effect was observed for the reported site. Finally, mutual correspondence between positional fluctuations noticeably increased with restraints on predicted allosteric site, whereas an opposite effect was observed for restraints applied on experimentally reported one. In view of these findings, it is clear that the perturbation of either one of two allosteric sites effected the dynamics of the receptor with a distinct and contrasting character. (c) 2022 Elsevier Ltd. All rights reserved.Conference Object Docking-Based Virtual Screening for Potential Activity Against Bacterial Pyruvate Kinase(Springer, 2017) Ergün, Çağla; Akten, Ebru Demet; Doruker, Pemra[Abstract Not Available]Article Citation - WoS: 18Citation - Scopus: 18Investigation of Allosteric Coupling in Human Beta(2)-Adrenergic Receptor in the Presence of Intracellular Loop 3(BMC, 2016) Özgür, Canan; Doruker, Pemra; Akten, Ebru DemetBackground: This study investigates the allosteric coupling that exists between the intra- and extracellular parts of human beta(2)-adrenergic receptor (beta(2)-AR) in the presence of the intracellular loop 3 (ICL3) which is missing in all crystallographic experiments and most of the simulation studies reported so far. Our recent 1 mu s long MD run has revealed a transition to the so-called very inactive state of the receptor in which ICL3 packed under the G protein's binding cavity and completely blocked its accessibility to G protein. Simultaneously an outward tilt of transmembrane helix 5 (TM5) caused an expansion of the extracellular ligand-binding site. In the current study we performed independent runs with a total duration of 4 mu s to further investigate the very inactive state with packed ICL3 and the allosteric coupling event (three unrestrained runs and five runs with bond restraints at the ligand-binding site). Results: In all three independent unrestrained runs (each 500 ns long) ICL3 preserved its initially packed/closed conformation within the studied time frame suggesting an inhibition of the receptor's activity. Specific bond restraints were later imposed between some key residues at the ligand-binding site which have been experimentally determined to interact with the ligand. Restraining the binding site region to an open state facilitated ICL3 closure whereas a relatively constrained/closed binding site hindered ICL3 packing. However the reverse operation i.e. opening of the packed ICL3 could not be realized by restraining the binding site region to a closed state. Thus any attempt failed to free the ICL3 from its locked state due to the presence of persistent hydrogen bonds. Conclusions: Overall our simulations indicated that starting with very inactive states the receptor stayed almost irreversibly inhibited which in turn decreased the overall mobility of the receptor. Bond restraints which represented the geometric restrictions caused by ligands of various sizes when bound at the ligand-binding site induced the expected conformational changes in TM5 TM6 and consequently ICL3. Still once ICL3 was packed the allosteric coupling became ineffective due to strong hydrogen bonds connecting ICL3 to the core of the receptor.
