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: 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, Kemal
Amaç: 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.
Citation Count: 18
Absolute configuration and biological profile of pyrazoline enantiomers as MAO inhibitory activity
(Wiley, 2019) Yelekçi, Kemal; Sarıgül, Sevgi; Bultinck, Patrick; Herrebout, Wouter; Doğan, İlknur; Yelekçi, Kemal; Uçar, Gülberk; Kelekçi, Nesrin Gökhan
A new racemic pyrazoline derivative was synthesized and resolved to its enantiomers using analytic and semipreparative high-pressure liquid chromatography. The absolute configuration of both fractions was established using vibrational circular dichroism. The in vitro monoamine oxidase (MAO) inhibitory profiles were evaluated for the racemate and both enantiomers separately for the two isoforms of the enzyme. The racemic compound and both enantiomers were found to inhibit hMAO-A selectively and competitively. In particular the R enantiomer was detected as an exceptionally potent and a selective MAO-A inhibitor (K-i = 0.85 x 10(-3) +/- 0.05 x 10(-3) mu M and SI: 2.35 x 10(-5)) whereas S was determined as poorer compound than R in terms of K-i and SI (0.184 +/- 0.007 and 0.001). The selectivity of the enantiomers was explained by molecular modeling docking studies based on the PDB enzymatic models of MAO isoforms.
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: 2
Aryl butenoic acid derivatives as a new class of histone deacetylase inhibitors: synthesis in vitro evaluation and molecular docking studies
(Scientific Technical Research Council Turkey-Tubitak, 2014) Yelekçi, Kemal; Seven, özlem; Eymur, Guluzar; Tatar, Gamze Bora; Erden, Didem Dayangaç; Yelekçi, Kemal; Yurter, Hayat; Demir, Ayhan S.
New aryl butenoic acid derivatives have been synthesized by combining hydroxy- or methoxy-substituted phenyl rings as the capping group with a double bond in the short linker as well as metal binding groups enoic ester and salts bearing either methyl or morpholine. These compounds have been shown to possess promising histone deacetylase inhibition activities via in vitro fluorometric assay and molecular docking studies.
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: 0
The Association of Gvhd With Hla Dr Alleles, Ifn-Gamma, Tgf-Beta, And Mbl2 Gene Polymorphism
(Wiley, 2019) Oğuz, Rusdu; Çiftçi, Hayriye Şentürk; Gökçe, Muge; Öğret, Yeliz; Karadeniz, Sedat Tanju; Pehlivan, Sacide; Aydın, Filiz
[Abstract Not Available]
Citation Count: 0
Atomic collisions and free lepton pair production
(2005) Güçlü, Mehmet Cem; Yılmaz, Melek
In this work we have calculated the total cross sections of electron-positron pair production for the collisions of fully stripped gold ions for various energies. We have also compared our calculation with other methods.
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: 5
Calculating Level Densities of Heavy Nuclei by the Shell Model Monte Carlo Method
(Academic Press Inc Elsevier Science, 2014) Alhassid, Yoram; Özen, Cem; Nakada, Hitoshi
The microscopic calculation of nuclear level densities in the presence of correlations is a difficult many-body problem. The shell model Monte Carlo method provides a powerful technique to carry out such calculations using the framework of the configuration-interaction shell model in spaces that are many orders of magnitude larger than spaces that can be treated by conventional methods. We present recent applications of the method to the calculation of level densities and their collective enhancement factors in heavy nuclei. The calculated level densities are in close agreement with experimental data.
Citation Count: 18
Carboxylic acid derivatives display potential selectivity for human histone deacetylase 6: Structure-based virtual screening molecular docking and dynamics simulation studies
(Elsevier Science, 2018) Yelekçi, Kemal; Yelekçi, Kemal
Human histone deacetylase 6 (HDAC6) has been shown to play a major role in oncogenic cell transformation via deacetylation of alpha-tubulin making it a viable target of anticancer drug design and development. The crystal structure of HDAC6 catalytic domain 2 has been recently made available providing avenues for structure-based drug design campaign. Here in our continuous effort to identify potentially selective HDAC6 inhibitors structure-based virtual screening of similar to 72 461 compounds was carried out using Autodock Vina. The top 100 compounds with calculated Delta G < -10 kcal/mol were manually inspected for binding mode orientation. Furthermore the top 20 compounds with reasonable binding modes were evaluated for selectivity by further docking against HDAC6 and HDAC7 using Autodock4. Four compounds with a carboxylic fragment displayed potential selectivity for HDAC6 over HDAC7 and were found to have good druglike and ADMET properties. Their docking complexes were then submitted to 10 ns-molecular dynamics (MD) simulation using nanoscale MD (NAMD) software to examine the stability of ligand binding modes. These predicted inhibitors remained bound to HDAC6 in the presence of water and ions and the root-mean-square deviation (RMSD) radius of gyration (Rg) and nonbond distance (protein-ligand) profiles suggested that they might be stable over time of the simulation. This study may provide scaffolds for further lead optimization towards the design of HDAC6 inhibitors with improved selectivity. (C) 2018 Elsevier Ltd. All rights reserved.
Citation Count: 16
Cation Effect on Slow Release from Alginate Beads: A Fluorescence Study
(Springer/Plenum Publishers, 2014) Kaygusuz, Hakan; Erim, F. Bedia; Pekcan, Önder; Evingür, Gülşen Akin
In this study spherical alginate beads containing pyranine (P-y) as a fluorescence probe were prepared by ionotropic gelation of a sodium alginate solution. The steady state fluorescence technique was used to study pyranine release from the alginate beads crosslinked with calcium barium and aluminum ions respectively. The slow release of P-y was observed with the time drive mode of the spectrophotometer at 512 nm. Fluorescence emission intensity (I-p) from P-y was monitored during the release process and the encapsulation efficiency (EE) of pyranine from the alginate beads was calculated. The Fickian Diffusion model was used to measure the release coefficients D-sl. It was seen that the slow release coefficients of pyranine from the alginate beads crosslinked with Ca2+ Ba2+ and Al3+ ions increased in the following order: D-sl (Al3+)> D-sl (Ca2+)> D-sl (Ba2+). In contrast the initial amount of pyranine and EE into the beads showed the reverse behavior.
Citation Count: 2
Characterization of MWCNT-TiO2 Qps and TiO2 QDs in self-assembled films
(Elsevier, 2017) Akkaya Arier, Ümit Özlem; Uysal, Bengü Özuğur
In this study the solution which includes TiO2 quantum dots (QDs) was mixed with the multi-wall carbon nanotubes (MWCNTs) to prepare MWCNT-TiO2 QDs composite films. The effect of microstructures on the structural and optical properties of MWCNT-TiO2 QDs composite films was evaluated. The activation energy for crystallite growth of TiO2 QDs which are produced in brookite phases was calculated as 20.3 kJ/mol. The properties of MWCNT-TiO2 QDs composite films were characterized by X-ray diffraction (XRD) scanning electron microscopy (SEM) atomic force microscopy (AFM) and ultraviolet-visible absorption spectroscopy (UV-vis). (C) 2017 Elsevier GmbH. All rights reserved.
Citation Count: 30
Cis-cyclopropylamines as mechanism-based inhibitors of monoamine oxidases
(Wiley-Blackwell, 2015) Yelekçi, Kemal; Yelekçi, Kemal; Borrello, Maria Teresa; Ganesan, A.; Semina, Elena; De Kimpe, Norbert; Mangelinckx, Sven; Ramsay, Rona R.
Cyclopropylamines inhibitors of monoamine oxidases (MAO) and lysine-specific demethylase (LSD1) provide a useful structural scaffold for the design of mechanism-based inhibitors for treatment of depression and cancer. For new compounds with the less common cis relationship and with an alkoxy substituent at the 2-position of the cyclopropyl ring the apparent affinity determined from docking experiments revealed little difference between the enantiomers. Using the racemate kinetic parameters for the reversible and irreversible inhibition of MAO were determined. No inhibition of LSD1 was observed. For reversible inhibition most compounds gave high IC50 values with MAO A but sub-micromolar values with MAO B. After pre-incubation of the cyclopropylamine with the enzyme the inhibition was irreversible for both MAOA and MAOB and the activity was not restored by dilution. Spectral changes during inactivation of MAOA included bleaching at 456nm and an increased absorbance at 400nm consistent with flavin modification. These derivatives are MAOB-selective irreversible inhibitors that do not show inhibition of LSD1. The best inhibitor was cis-N-benzyl-2-methoxycyclopropylamine with an IC50 of 5nm for MAOB and 170nm for MAOA after 30min pre-incubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine so may be studied as a lead for selective inhibitors of MAOB that do not inhibit LSD1.
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: 0
Collective enhancement of nuclear state densities by the shell model Monte Carlo approach
(IOP Publishing Ltd, 2015) Özen, Cem; Alhassid, Yoram; Nakada, Hitoshi
The shell model Monte Carlo (SMMC) approach allows for the microscopic calculation of statistical and collective properties of heavy nuclei using the framework of the configuration-interaction shell model in very large model spaces. We present recent applications of the SMMC method to the calculation of state densities and their collective enhancement factors in rare-earth nuclei.
Citation Count: 1
Collectivity in Heavy Nuclei in the Shell Model Monte Carlo Approach
(EDP Sciences, 2014) Özen, Cem; Alhassid, Yoram; Nakada, Hitoshi
The microscopic description of collectivity in heavy nuclei in the framework of the configuration-interaction shell model has been a major challenge. The size of the model space required for the description of heavy nuclei prohibits the use of conventional diagonalization methods. We have overcome this difficulty by using the shell model Monte Carlo (SMMC) method which can treat model spaces that are many orders of magnitude larger than those that can be treated by conventional methods. We identify a thermal observable that can distinguish between vibrational and rotational collectivity and use it to describe the crossover from vibrational to rotational collectivity in families of even-even rare-earth isotopes. We calculate the state densities in these nuclei and find them to be in close agreement with experimental data. We also calculate the collective enhancement factors of the corresponding level densities and find that their decay with excitation energy is correlated with the pairing and shape phase transitions.
Citation Count: 0
COMP 297-Experimental and molecular docking simulation studies of Histone deacetylases (HDACs) enzyme inhibitors
(Amer Chemical Soc, 2007) Yelekçi, Kemal; Bora, Gamze; Dayangaç-Erden, Didem; Ayhan, Peruze; Dalkara, Sevim; Demir, Ayhan S.; Erdem-Yurter, Hayat
[Abstract Not Available]
Citation Count: 0
Comparison of cation effects on phase transitions of kappa and iota carrageenan
(European Polymer Federation, 2010) Tari, Özlem; Pekcan, Önder
Phase transitions of kappa and iota carrageenan in KCl NaCl and CaCl2 solutions were separately studied during heating and cooling processes by using fluorescence technique. Scattered light I-SC and fluorescence intensity I was monitored against temperature to determine the critical transition temperatures and exponents. Kappa and iota carrageenans with monovalent (KCl NaCl) salt system presented only coil to double helix (c-h) and double helix to coil (h-c) transitions upon cooling and heating processes respectively. Two transition regions were observed in both heating and cooling of the iota carrageenan in CaCl2 solution while in kappa carrageenan only (c-h) and (h-c) transitions was detected. During heating dimers decompose into double helices by making (d-h) transition. At the high temperature region (h-c) transition takes place. During cooling back transitions repeat themselves. A hysteresis was observed between (h-c) and (c-h) for the kappa and iota carrageenan salt system (except CaCl2) respectively. Dimer to double helix (d-h) and double helix to dimer (h-d) transitions were observed for iota carrageenan in CaCl2 salt. The gel fraction exponent beta was measured and found to be in accord with the classical Flory-Stockmayer Model for both kappa and iota carrageenan salt systems.
Citation Count: 6
A comparison of fluorescence and UV-visible spectrometry techniques for thermal phase transitions of agarose gels
(Springer, 2015) Arda, Ertan; Kara, Selim; Mergen, Ömer Bahadır; Pekcan, Önder
In this study thermoreversible phase transitions of high (HMP) and low (LMP) melting point agarose gels were investigated by using the UV-vis and fluorescence spectroscopy techniques. Pyranine was added to the aqueous solution of agarose as a fluorescence-probe. Transmitted light (I (tr)) and fluorescence emission (I (fl)) intensities from the gel samples with different agarose concentrations were monitored during the heating (gel-sol) and cooling (sol-gel) processes. For the both techniques gel-sol (T (gs)) and sol-gel (T (sg)) transition temperatures were determined from the first derivatives of the sigmoidal transition paths. It was observed that the critical transition temperatures obtained from UV-vis and fluorescence data slightly increased depending on the agarose type and concentration and those values were found to be in accord with each other. Transition activation energies were determined using the Arrhenius type equation and were found to be strongly correlated with the agarose content in the gel system. The produced gel-sol (Delta E (gs)) and sol-gel (Delta E (sg)) transition energies from the fluorescence data were found to be lower than that of the UV-vis data which was attributed to the temperature-dependent fluorescence quenching effect.
Citation Count: 5
Computational Analysis of a Zn-Bound Tris(imidazolyl) Calix[6]arene Aqua Complex: Toward Incorporating Second-Coordination Sphere Effects into Carbonic Anhydrase Biomimetics
(Amer Chemical Soc, 2013) Eşsiz, Şebnem; Eşsiz, Şebnem; Wong, Sergio E.; Lau, Edmond Y.; Valdez, Carlos A.; Satcher, Joe H. Jr.; Aines, Roger D.; Lightstone, Felice C.
Molecular dynamics simulations and quantum-mechanical calculations were performed to characterize a supra-molecular tris(imidazolyl) calix[6]arene Zn2+ aqua complex as a biomimetic model for the catalyzed hydration of carbon dioxide to bicarbonate H2O + CO2 -> H+ + HCO3-. On the basis of potential-of-mean-force (PMF) calculations stable conformations had distorted 3-fold symmetry and supported either one or zero encapsulated water molecules. The conformation with an encapsulated water molecule is calculated to be lower in free energy than the conformation with an empty cavity (Delta G = 1.2 kcal/mol) and is the calculated free-energy minimum in solution. CO2 molecule partitioning into the cavity is shown to be very facile proceeding with a barrier of 1.6 kcal/mol from a weak encounter complex which stabilizes the species by about 1.0 kcal/mol. The stabilization energy of CO2 is calculated to be larger than that of H2O (Delta Delta G = 1.4 kcal/mol) suggesting that the complex will preferentially encapsulate CO2 in solution. In contrast the PMF for a bicarbonate anion entering the cavity is calculated to be repulsive in all nonbonding regions of the cavity due to the diameter of the calix[6]arene walls. Geometry optimization of the Zn-bound hydroxide complex with an encapsulated CO2 molecule showed that multiple noncovalent interactions direct the reactants into optimal position for nucleophilic addition to occur. The calixarene complex is a structural mimic of the hydrophilic/hydrophobic divide in the enzyme providing a functional effect for CO2 addition in the catalytic cycle. The results show that Zn-binding calix[6]arene scaffolds can be potential synthetic biomimetics for CO2 hydration catalysis both in terms of preferentially encapsulating CO2 from solution and by spatially fixing the reactive species inside the cavity.

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