Mühendislik ve Doğa Bilimleri Fakültesi

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Citation - WoS: 23
Citation - Scopus: 26
Absolute Configuration and Biological Profile of Pyrazoline Enantiomers as Mao Inhibitory Activity
(Wiley, 2019) Goksen, Umut Salgin; 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 - WoS: 12
Citation - Scopus: 15
Accurate Refinement of Docked Protein Complexes Using Evolutionary Information and Deep Learning
(Imperıal College Press, 2016) Akbal-Delibas, Bahar; Farhoodi, Roshanak; Pomplun, Marc; Haspel, Nurit
One of the major challenges for protein docking methods is to accurately discriminate native-like structures from false positives. Docking methods are often inaccurate and the results have to be refined and re-ranked to obtain native-like complexes and remove outliers. In a previous work we introduced AccuRefiner a machine learning based tool for refining protein-protein complexes. Given a docked complex the refinement tool produces a small set of refined versions of the input complex with lower root-mean-square-deviation (RMSD) of atomic positions with respect to the native structure. The method employs a unique ranking tool that accurately predicts the RMSD of docked complexes with respect to the native structure. In this work we use a deep learning network with a similar set of features and five layers. We show that a properly trained deep learning network can accurately predict the RMSD of a docked complex with 1.40 angstrom error margin on average by approximating the complex relationship between a wide set of scoring function terms and the RMSD of a docked structure. The network was trained on 35000 unbound docking complexes generated by RosettaDock. We tested our method on 25 different putative docked complexes produced also by RosettaDock for five proteins that were not included in the training data. The results demonstrate that the high accuracy of the ranking tool enables AccuRefiner to consistently choose the refinement candidates with lower RMSD values compared to the coarsely docked input structures.
Citation - WoS: 1
Citation - Scopus: 1
Across Dimensions: Two- and Three-Dimensional Phase Transitions From the Iterative Renormalization-Group Theory of Chains
(2020) Keçoğlu, İbrahim; Berker, A. Nihat
Sharp two- and three-dimensional phase transitional magnetization curves are obtained by an iterative renormalization-group coupling of Ising chains, which are solved exactly. The chains by themselves do not have a phase transition or nonzero magnetization, but the method reflects crossover from temperaturelike to fieldlike renormalization-group flows as the mechanism for the higher-dimensional phase transitions. The magnetization of each chain acts, via the interaction constant, as a magnetic field on its neighboring chains, thus entering its renormalization-group calculation. The method is highly flexible for wide application.
Citation - WoS: 8
Citation - Scopus: 9
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 - WoS: 1
Citation - Scopus: 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 - WoS: 57
Citation - Scopus: 65
Beams: Backbone Extraction and Merge Strategy for the Global Many-To Alignment of Multiple Ppi Networks
(Oxford University Press, 2014) Alkan, Ferhat; Erten, Cesim
Motivation: Global many-to-many alignment of biological networks has been a central problem in comparative biological network studies. Given a set of biological interaction networks the informal goal is to group together related nodes. For the case of protein-protein interaction networks such groups are expected to form clusters of functionally orthologous proteins. Construction of such clusters for networks from different species may prove useful in determining evolutionary relationships in predicting the functions of proteins with unknown functions and in verifying those with estimated functions. Results: A central informal objective in constructing clusters of orthologous proteins is to guarantee that each cluster is composed of members with high homological similarity usually determined via sequence similarities and that the interactions of the proteins involved in the same cluster are conserved across the input networks. We provide a formal definition of the global many-to-many alignment of multiple protein-protein interaction networks that captures this informal objective. We show the computational intractability of the suggested definition. We provide a heuristic method based on backbone extraction and merge strategy (BEAMS) for the problem. We finally show through experiments based on biological significance tests that the proposed BEAMS algorithm performs better than the state-of-the-art approaches. Furthermore the computational burden of the BEAMS algorithm in terms of execution speed and memory requirements is more reasonable than the competing algorithms.
Citation - WoS: 12
Citation - Scopus: 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 - WoS: 15
Citation - Scopus: 19
Campways: Constrained Alignment Framework for the Comparative Analysis of a Pair of Metabolic Pathways
(Oxford University Press, 2013) Abaka, Gamze; Biyikoglu, Turker; Erten, Cesim
Motivation: Given a pair of metabolic pathways an alignment of the pathways corresponds to a mapping between similar substructures of the pair. Successful alignments may provide useful applications in phylogenetic tree reconstruction drug design and overall may enhance our understanding of cellular metabolism. Results: We consider the problem of providing one-to-many alignments of reactions in a pair of metabolic pathways. We first provide a constrained alignment framework applicable to the problem. We show that the constrained alignment problem even in a primitive setting is computationally intractable which justifies efforts for designing efficient heuristics. We present our Constrained Alignment of Metabolic Pathways (CAMPways) algorithm designed for this purpose. Through extensive experiments involving a large pathway database we demonstrate that when compared with a state-of-the-art alternative the CAMPways algorithm provides better alignment results on metabolic networks as far as measures based on same-pathway inclusion and biochemical significance are concerned. The execution speed of our algorithm constitutes yet another important improvement over alternative algorithms.
Citation - WoS: 18
Citation - Scopus: 19
Carboxylic Acid Derivatives Display Potential Selectivity for Human Histone Deacetylase 6: Structure-Based Virtual Screening Molecular Docking and Dynamics Simulation Studies
(Elsevier Science, 2018) Uba, Abdullahi Ibrahim; 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 - WoS: 17
Citation - Scopus: 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 - WoS: 33
Citation - Scopus: 33
Cis-Cyclopropylamines as Mechanism-Based Inhibitors of Monoamine Oxidases
(Wiley-Blackwell, 2015) Malcomson, Thomas; 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 - WoS: 9
Citation - Scopus: 9
Complete Density Calculations of Q-State Potts and Clock Models: Reentrance of Interface Densities Under Symmetry Breaking
(Amer Physical Soc, 2020) Artun, E. Can; Berker, A. Nihat
All local bond-state densities are calculated for q-state Potts and clock models in three spatial dimensions, d = 3. The calculations are done by an exact renormalization group on a hierarchical lattice, including the density recursion relations, and simultaneously are the Migdal-Kadanoff approximation for the cubic lattice. Reentrant behavior is found in the interface densities under symmetry breaking, in the sense that upon lowering the temperature, the value of the density first increases and then decreases to its zero value at zero temperature. For this behavior, a physical mechanism is proposed. A contrast between the phase transition of the two models is found and explained by alignment and entropy, as the number of states q goes to infinity. For the clock models, the renormalization-group flows of up to 20 energies are used.
Citation - WoS: 5
Citation - Scopus: 7
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) Koziol, Lucas; 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.
Citation - WoS: 48
Citation - Scopus: 61
A Computerized Recognition System for the Home-Based Physiotherapy Exercises Using an Rgbd Camera
(IEEE, 2014) Ar, İlktan; Akgül, Yusuf Sinan
Computerized recognition of the home based physiotherapy exercises has many benefits and it has attracted considerable interest among the computer vision community. However most methods in the literature view this task as a special case of motion recognition. In contrast we propose to employ the three main components of a physiotherapy exercise (the motion patterns the stance knowledge and the exercise object) as different recognition tasks and embed them separately into the recognition system. The low level information about each component is gathered using machine learning methods. Then we use a generative Bayesian network to recognize the exercise types by combining the information from these sources at an abstract level which takes the advantage of domain knowledge for a more robust system. Finally a novel postprocessing step is employed to estimate the exercise repetitions counts. The performance evaluation of the system is conducted with a new dataset which contains RGB (red green and blue) and depth videos of home-based exercise sessions for commonly applied shoulder and knee exercises. The proposed system works without any body-part segmentation bodypart tracking joint detection and temporal segmentation methods. In the end favorable exercise recognition rates and encouraging results on the estimation of repetition counts are obtained.
Citation - WoS: 2
Citation - Scopus: 3
Corrected Panel-Reactive Antibody Positivity Rates for Hypersensitized Patients in Turkish Population With Calculated Panel-Reactive Antibody Software
(Elsevier Science Inc, 2017) Karadeniz, Sedat Tanju; Akgül, Sebahat Usta; Öğret, Yeliz; Çiftçi, Hayriye Şentürk; Bayraktar, Adem; Bakkaloğlu, Hüseyin; Çalışkan, Yaşar Kerem; Yelekçi, Kemal; Türkmen, Aydin; Aydın, Ali Emin; Oğuz, Fatma Savran; Çarin, Mahmut Nezih; Aydın, Filiz
however the rate was 86.2% using the cPRA. Discussion. cPRA shows the rate of the rejected donors according to all unacceptable antigens. The need for a list of unacceptable antigens in place of the PRA positivity rate is a real change in the sensitization-dependent calculation as cPRA positivity rate. Conclusion. In principal implementation of cPRA will encourage many centers and laboratories to adopt a standard measurement of sensitization in Turkey. It will increase the chances of better donor match particularly for hypersensitized patients by the creation of an unacceptable mismatch program using cPRA software.
Citation - WoS: 51
Citation - Scopus: 55
Crossover From Vibrational To Rotational Collectivity in Heavy Nuclei in the Shell-Model Monte Carlo Approach
(Amer Physical Soc., 2013) Özen, Cem; Alhassid, Yoram; Nakada, Hitoshi
Heavy nuclei exhibit a crossover from vibrational to rotational collectivity as the number of neutrons or protons increases from shell closure towards midshell but the microscopic description of this crossover has been a major challenge. We apply the shell model Monte Carlo approach to families of even-even samarium and neodymium isotopes and identify a microscopic signature of the crossover from vibrational to rotational collectivity in the low-temperature behavior of < J(2)>(T) where J is the total spin and T is the temperature. This signature agrees well with its values extracted from experimental data. We also calculate the state densities of these nuclei and find them to be in very good agreement with experimental data. Finally we define a collective enhancement factor from the ratio of the total state density to the intrinsic state density as calculated in the finite-temperature Hartree-Fock-Bogoliubov approximation. The decay of this enhancement factor with excitation energy is found to correlate with the pairing and shape phase transitions in these nuclei. DOI: 10.1103/PhysRevLett.110.042502
Citation - WoS: 15
Citation - Scopus: 17
Crystallographic Structure Versus Homology Model: a Case Study of Molecular Dynamics Simulation of Human and Zebrafish Histone Deacetylase 10
(Taylor & Francis, 2020) Uba, Abdullahi İbrahim; Yelekçi, Kemal
Histone deacetylase (HDAC) 10 has been implicated in the pathology of various cancers and neurodegenerative disorders, making the discovery of novel inhibitors of the isoform an important endeavor. However, the unavailability of crystallographic structure of human HDAC10 (hHDAC10) hinders structure-based drug design effort. Previously, we reported the homology modeled structure of human HDAC10 built using the crystallographic structure of Danio rerio (zebrafish) HDAC10 (zHDAC10) (Protein Data Bank (PDB) ID; 5TD7, released on 24 May 2017) as a template. Here, in continuation with our study, both hHDAC10 and zHDAC10, and their respective complexes with trichostatin A (TSA), quisinostat, and the native ligand (in 5TD7), 7-[(3-aminopropyl)amino]-1,1,1-trifluoroheptane-2,2-diol (PDB ID; FKS) were submitted to 100 ns-long unrestrained molecular dynamics (MD) simulations. Comparative analyses of the MD trajectories revealed that zHDAC10 and its complexes displayed higher stability than hHDAC10 and its corresponding complexes over time. Nonetheless, docking of active and inactive set molecules revealed that more reliable conformations of hHDAC10 could be obtained at an extended time period. This study may shed more light on the reliability of hHDAC10 modeled structure for use in selective inhibitor design.Communicated by Ramaswamy H. Sarma.
Citation - WoS: 6
Citation - Scopus: 8
The Design of Potent Hiv-1 Integrase Inhibitors by a Combined Approach of Structure-Based Virtual Screening and Molecular Dynamics Simulation
(Taylor & Francis Ltd, 2018) Samorlu, Augustine S.; Yelekçi, Kemal; Uba, Abdullahi Ibrahim
Bu araştırmanın amacı, AIDS olarak bilinen insan bağışıklık sistemine etki eden, duraksamayan ve depresif bir hastalığa neden olan HIV-1'in tedavisi için potansiyel inhibitörleri elde etmektir. HIV-1 integraz inhibitörleri, HIV-1 enfeksiyonunun tedavisinde çok önemlidir. İntegraz enziminin (IN) inhibe edilmesi HIV-1 virüsünün çoğalma işleminin sonlandırılmasına neden olur. Böylece yaşam döngüsüne son verir. Bu inhibitörleri elde etmek için bilgisayar destekli in silico yaklaşım kullanılmıştır. Temelde, Otava Kimya Kütüphanesi tarandı ve inhibitör tasarımında kullanılan sistematik yaklaşımlar uygulandı, böylece dört güçlü integraz inhibitörü bulundu. İnhibitörlerin enzime bağlanma değerleri PyRx ve AutoDock 4.2 doklama programları kullanılarak gerçekleştirildi. Çalışmada bir kimyasalın güçlü bir inhibitör olabilmesi için hesaplanan serbest bağ enerjisi = -8.00 kcal / mol veya daha az olması ve integrazın aktif bölgesinde bulunan 3 önemli amino asidinden herhangi biri ile de etkileşimde bulunması kriterine uyulmuştur. Discovery Studio Visualizer, inhibitörlerin yapısını çizmekte, inhibitörü komplekslerinin resimlerini üretmekte, enzim ve inhibitör arasındaki etkileşimin türünü belirlememizi sağlayan 2D ve 3D yapıları görüntülemek için kullanıldı. Elde edilen dört güçlü inhibitörden, kendimizin tasarladığı moleküllerden (Ki= 652.83 nanomolar bir ve bağlanma serbest enerjisi -8.44kcal / mol), kalan üç inhibitörde, Otava Kimya Kütüphanesi'nde tarandı ve Otava koduyla parantez içerisinde listelenmiştir. Bunların inhibisyon sabiti ve bağlanma enerjileri sırasıyla; 107320240, Ki=131.7nm, -9.39kcal/ mol; 109750115, Ki= 44.19nm, -10.03kcal / mol; 111150115 Ki = 395.19nm, -8.74kcal / mol olarak bulunmuştur.
Citation - WoS: 7
Citation - Scopus: 12
Design, Synthesis and Hmao Inhibitory Screening of Novel 2-Pyrazoline Analogues
(Bentham Science Publ Ltd, 2017) Evranos-Aksöz, Begüm; Uçar, Gülberk; Yelekçi, Kemal
Aim and Objective: MAO inhibitors have a significant effect on the nervous system since they act in regulation of neurotransmitter concentrations. Neurotransmitter levels are critical for a healthy nervous system. MAO inhibitors can be used in the treatment of neurological disorders such as depression, Parkinson's disease and Alzheimer's disease, as the increase or decrease of some neurotransmitter concentrations is associated with these neurological disorders. This study was conducted to discover new and active MAO inhibitor drug candidates. Materials and Methods: New pyrazoline derivatives have been designed with the molecular docking approach and interactions of our compounds with the MAO enzyme have been investigated using the Autodock 4.2 program. The designed pyrazoline derivative compounds were synthesized by the reaction of the chalcones and hydrazides in ethanol. hMAO inhibitory activities of the newly synthesized compounds were investigated by fluorimetric method. In vitro cytotoxicity of five most potent inhibitors were tested in HepG2 cells. Results: (3-(5-bromo-2-hydroxyphenyl)-5-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5i) and (3-(2-hydroxy-4-methoxy phenyl)-5-p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5l) inhibited hMAO-A more potently than moclobemide (Ki values are 0.004 +/- 0.001 and 0.005 +/- 0.001, respectively). The same two compounds, 5i and 5l, inhibited hMAO-A more selectively than moclobemide (SI values are 5.55x10(-5) and 0.003, respectively). Both of these compounds were found non toxic at 1 mu M, 5 mu M and 25 mu M concentrations. Conclusion: Two of the newly synthesized compounds, (3-(5-bromo-2-hydroxyphenyl)-5-(4-methoxyphenyl)- 4,5-dihydropyrazol-1-yl)(phenyl) methanone and (3-(2-hydroxy-4-methoxy phenyl)5- p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone were found to be promising MAO-A inhibitors due to their high inhibitory potency, high selectivity and low toxicity.
Citation - WoS: 7
Citation - Scopus: 8
Design, Synthesis and in Vitro Cytotoxic Activity of New 6,9-Disubstituted Purine Analogues
(Slovensko Kemijsko Drustvo, 2020) Kuçükdumlu, Aslıgül; Tunçbilek, Meral; Bilget Güven, Ebru; Atalay, Rengül Çetin
A series of new 6,9-disubstituted purine analogs with 4-substituted piperazine at C-6 and 4-substituted benzyl at N-9 were designed and synthesized in four steps. All synthesized compounds (7-26) were screened initially for their in vitro anticancer activity on Huh7 liver, HCT116 colon and MCF7 breast carcinoma cell lines. Cytotoxic bioactivity studies revealed that all compounds screened, with compound 19 being the exception, were found to have promising cytotoxic activities at IC50 range of 0.05-21.8 mu M against cancer cells Huh7, HCT116 and MCF7. Among the prepared purine analogs, two of them (12 and 22) exhibited excellent cytotoxic activities, with IC50 0.08-0.13 mu M, on Huh7 cells comparable to camptothecin (CPT) and better than cladribine, fludarabine and 5-FU. Afterwards, the evaluation of cytotoxicity of the most potent purine analogs was screened against further hepatocellular cancer (HCC) cell lines. The 6-(4-(4-trifluoromethylphenyl)piperazine (12) and 6-(4-(3,4-dichlorophenyl)piperazine analogs (25) displayed a significant IC50 values (IC50 < 0.1-0.13 mu M) comparable to CPT and better cytotoxic bioactivity when compared with 5-FU, cladribine and fludarabine on HCC cells (Huh7 and HepG2).

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