Browsing by Author "Yelekçi, Kemal"

Now showing 1 - 20 of 26

Citation - WoS: 22
Citation - Scopus: 25
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: 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: 50
Citation - Scopus: 59
A Computational Study on the Amine-Oxidation Mechanism of Monoamine Oxidase: Insight Into the Polar Nucleophilic Mechanism
(Royal Soc Chemistry, 2006) Sağ Erdem, Safiye; Karahan, Özlem; Yıldız, İbrahim; Yelekçi, Kemal
The proposed polar nucleophilic mechanism of MAO was investigated using quantum chemical calculations employing the semi-empirical PM3 method. In order to mimic the reaction at the enzyme's active site the reactions between the flavin and the p-substituted benzylamine substrate analogs were modeled. Activation energies and rate constants of all the reactions were calculated and compared with the published experimental data. The results showed that electron-withdrawing groups at the para position of benzylamine increase the reaction rate. A good correlation between the log of the calculated rate constants and the electronic parameter (sigma) of the substituent was obtained. These results agree with the previous kinetic experiments on the effect of p-substituents on the reduction of MAO-A by benzylamine analogs. In addition the calculated rate constants showed a correlation with the rate of reduction of the flavin in MAO-A. In order to verify the results obtained from the PM3 method single-point B3LYP/6-31G*//PM3 calculations were performed. These results demonstrated a strong reduction in the activation energy for the reaction of benzylamine derivatives having electron-withdrawing substituents which is in agreement with the PM3 calculations and the previous experimental QSAR study. PM3 and B3LYP/6-31G* energy surfaces were obtained for the overall reaction of benzylamine with flavin. Results suggest that PM3 is a reasonable method for studying this kind of reaction. These theoretical findings support the proposed polar nucleophilic mechanism for MAO-A.
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: 59
Citation - Scopus: 57
Docking Studies on Monoamine Oxidase-B Inhibitors: Estimation of Inhibition Constants (k-I) of a Series of Experimentally Tested Compounds
(Pergamon-Elsevier Science Ltd, 2005) Toprakçı, Mustafa; Yelekçi, Kemal
Monoamine oxidase (EC1.4.3.4
Ekmek Mayası (saccharomyces Cerevisiae) Yardımı ile L-3,4- Dihitroksifenil Alanin (l-dopa) için Yeni Bir Sentez Yöntemi
(TUBITAK Scientific & Technical Research Council Turkey, 1997) Yelekçi, Kemal; Hamamcı, Haluk; Kahraman, M. Vezir; Karataş, Sevim
Ekmek mayası (saccharomyces cerevisiae) kolay ve ucuz bulunan bir reaktif olmasına karşın, organik kimyada yaptığı tepkimeler hem ilginç hem de diğer sentez yöntemleri ile yapılması ya imkansız ya da çok zordur. Bu amaçla klasik organik sentez yöntemleri ve maya kullanılarak daha önce sentezi bu yolla denenmeyen, anti parkinson ilacı L-3,4-Dihidroksifenilalanin'in sentezine yönelik ikisi orjinal dört önemli substurat hazırlanacak ve bu substratlar üzerinde bulunan karbon karbon çift bağı ekmek mayası ile stereospesifık olarak indirgenmeye çalışılacaktır.
Epitope Based Hla Matching by Using Antibody Reactivity With High Resolution Allele Typing and Hlamatchmaker Algorithm Based Software
(Wiley, 2017) Karadeniz, Sedat Tanju; Akgül, Sebahat Usta; Çiftçi, Hayriye Şentürk; Öğret, Yeliz; Oğuz, Fatma; Yelekçi, Kemal; Aydın, Filiz
[Abstract Not Available]
Citation - WoS: 11
Citation - Scopus: 20
Evaluation of Selective Human Mao Inhibitory Activities of Some Novel Pyrazoline Derivatives
(SPRINGER WIEN, 2013) Salgin-Goksen, Umut; Yabanoglu-Ciftci, Samiye; Ercan, Ayse; Yelekçi, Kemal; Ucar, Gulberk; Gokhan-Kelekçi, Nesrin
A series of 1-[2-((5-methyl/chloro)-2-benzoxazolinone-3-yl)acetyl]-35-diaryl-45-dihydro-1H-pyrazole derivatives were prepared by reacting 2-((5-methyl/chloro)-2-benzoxazolinone-3-yl)acetylhydrazine with appropriate chalcones. The chemical structures of all compounds were confirmed by elemental analyses IR H-1 NMR and ESI-MS. All the compounds were investigated for their ability to selectively inhibit monoamine oxidase (MAO) by in vitro tests. MAO activities of the compounds were compared with moclobemide and selegiline and all the compounds were found to inhibit human MAO-A selectively. The inhibition profile was found to be competitive and reversible for all compounds by in vitro tests. Among the compounds examined compounds 5ae 5af and 5ag were more selective than moclobemide with respect to the K (i) values experimentally found. In addition the compound 5bg showed MAO-A inhibitor activity as well as moclobemide. A series of experimentally tested compounds (5ae-5ch) were docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The AUTODOCK 4.01 program was employed to perform automated molecular docking.
Citation - WoS: 10
Citation - Scopus: 10
Homology Modeling Andin Silicodesign of Novel and Potential Dual-Acting Inhibitors of Human Histone Deacetylases Hdac5 and Hdac9 Isozymes
(2020) Elmezayen, Ammar D.; Yelekçi, Kemal
Histone deacetylases (HDACs) are a group of enzymes that have prominent and crucial effect on various biological systems, mainly by their suppressive effect on transcription. Searching for inhibitors targeting their respective isoforms without affecting other targets is greatly needed. Some histone deacetylases have no crystal structures, such as HDAC5 and HDAC9. Lacking proper and suitable crystal structure is obstructing the designing of appropriate isoform selective inhibitors. Here in this study, we constructed human HDAC5 and HDAC9 protein models using human HDAC4 (PDB:2VQM_A) as a template by the means of homology modeling approach. Based on the Z-score of the built models, model M0014 of HDAC5 and model M0020 of HDAC9 were selected. The models were verified by MODELLER and validated using the Web-based PROCHECK server. All selected known inhibitors displayed reasonable binding modes and equivalent predicted Ki values in comparison to the experimental binding affinities (Ki/IC50). The known inhibitor Rac26 showed the best binding affinity for HDAC5, while TMP269 showed the best binding affinity for HDAC9. The best two compounds, CHEMBL2114980 and CHEMBL217223, had relatively similar inhibition constants against HDAC5 and HDAC9. The built models and their complexes were subjected to molecular dynamic simulations (MD) for 100 ns. Examining the MD simulation results of all studied structures, including the RMSD, RMSF, radius of gyration and potential energy suggested the stability and reliability of the built models. Accordingly, the results obtained in this study could be used for designing de novo inhibitors against HDAC5 and HDAC9. Communicated by Ramaswamy H. Sarma
Citation - WoS: 26
Citation - Scopus: 31
Homology Modeling of Human Histone Deacetylase 10 and Design of Potential Selective Inhibitors
(Taylor & Francis Inc, 2019) Uba, Abdullahi Ibrahim; Yelekçi, Kemal
Histone deacetylases (HDACs) are implicated in the pathology of various cancers, and their pharmacological blockade has proven to be promising in reversing the malignant phenotypes. However, lack of crystal structures of some of the human HDAC isoforms (e.g., HDAC10) hinders the design of the isoform-selective inhibitor. Here, the recently solved X-ray crystal structure of Danio rerio (zebrafish) HDAC10 (Protein Data Bank (PDB) ID; 5TD7, released on 24 May 2017) was retrieved from the PDB and used as a template structure to model the three-dimensional structure of human HDAC10. The overall quality of the best model (M0017) was assessed by computing its z-score-a measure of the deviation of the total energy of the structure with respect to an energy distribution derived from random conformations and by docking of known HDAC10 inhibitors to its catalytic cavity. Furthermore, to identify potential HDAC10-selective inhibitor ligand-based virtual screening was carried out against the ZINC database. The free modeled structure of HDAC10 and its complexes with quisinostat and the highest-ranked compound ZINC19749069 were submitted to molecular dynamics simulation. The comparative analysis of root-mean-squared deviation, root-mean-squared fluctuation, radius of gyration (Rg), and potential energy of these systems showed that HDAC10-ZINC19749069 complex remained the most stable over time. Thus, M0017 could be potentially used for structure-based inhibitor against HDAC10, and ZINC19749069 may provide a scaffold for further optimization. Communicated by Ramaswamy H. Sarma
Citation - WoS: 8
Citation - Scopus: 9
Human Dopamine Transporter: the First Implementation of a Combined in Silico/In Vitro Approach Revealing the Substrate and Inhibitor Specificities
(Taylor & Francis Inc, 2019) Djikic, Teodora; Marti, Yasmina; Spyrakis, Francesca; Lau, Thorsten; Benedetti, Paolo; Davey, Gavin; Schloss, Patrick; Yelekçi, Kemal
Parkinson's disease (PD) is characterized by the loss of dopamine-generating neurons in the substantia nigra and corpus striatum. Current treatments alleviate PD symptoms rather than exerting neuroprotective effect on dopaminergic neurons. New drugs targeting the dopaminergic neurons by specific uptake through the human dopamine transporter (hDAT) could represent a viable strategy for establishing selective neuroprotection. Molecules able to increase the bioactive amount of extracellular dopamine thereby enhancing and compensating a loss of dopaminergic neurotransmission and to exert neuroprotective response because of their accumulation in the cytoplasm are required. By means of homology modeling molecular docking and molecular dynamics simulations we have generated 3D structure models of hDAT in complex with substrate and inhibitors. Our results clearly reveal differences in binding affinity of these compounds to the hDAT in the open and closed conformations critical for future drug design. The established in silico approach allowed the identification of promising substrate compounds that were subsequently analyzed for their efficiency in inhibiting hDAT-dependent fluorescent substrate uptake through in vitro live cell imaging experiments. Taken together our work presents the first implementation of a combined in silico/in vitro approach enabling the selection of promising dopaminergic neuron-specific substrates.
Citation - WoS: 17
Citation - Scopus: 20
Identification of Potential Inhibitors of Human Methionine Aminopeptidase (type Ii) for Cancer Therapy: Structure-Based Virtual Screening, Admet Prediction and Molecular Dynamics Studies
(Elsevier, 2020) Weako, Jackson; Uba, Abdullahi Ibrahim; Keskin, Özlem; Gürsoy, Attila; Yelekçi, Kemal
Methionine Aminopeptidases MetAPs are divalent-cofactor dependent enzymes that are responsible for the cleavage of the initiator Methionine from the nascent polypeptides. MetAPs are classified into two isoforms: namely, MetAP1 and MetAP2. Several studies have revealed that MetAP2 is upregulated in various cancers, and its inhibition has shown to suppress abnormal or excessive blood vessel formation and tumor growth in model organisms. Clinical studies show that the natural product fumagillin, and its analogs are potential inhibitors of MetAP2. However, due to their poor pharmacokinetic properties and neurotoxicities in clinical studies, their further developments have received a great setback. Here, we apply structure-based virtual screening and molecular dynamics methods to identify a new class of potential inhibitors for MetAP2. We screened Otava's Chemical Library, which consists of about 3 200 000 tangible-chemical compounds, and meticulously selected the top 10 of these compounds based on their inhibitory potentials against MetAP2. The top hit compounds subjected to ADMET predictor using 3 independent ADMET prediction programs, were found to be drug-like. To examine the stability of ligand binding mode, and efficacy, the unbound form of MetAP2, its complexes with fumagillin, spiroepoxytriazole, and the best promising compounds compound-3369841 and compound-3368818 were submitted to 100 ns molecular dynamics simulation. Like fumagillin, spiroepoxytriazole, and both compound-3369841 and compound-3368818 showed stable binding mode over time during the simulations. Taken together, these uninherited-fumagillin compounds may serve as new class of inhibitors or provide scaffolds for further optimization towards the design of more potent MetAP2 inhibitors -development of such inhibitors would be essential strategy against various cancer types.
In Silico Design of Novel and Highly Selective Cyclooxygenase-2 Inhibitors
(Kadir Has Üniversitesi, 2014) Mehmetoğlu, Tuğba; Yelekçi, Kemal
For many years, prevention of inflammation is achieved by inhibition of both cyclooxygenase (COX) enzymes; the eventual outcome is gastrointestinal toxicity. Selective inhibitor design for COX-2 initialized just after discovery of two distinct types of COX enzymes. Both isoforms of COX show great similarities at the active sites. It is still essential to find more potent, more selective and reversible COX-2 inhibitors. Crystallographic structures of COX-1 (pdb code: 1Q4G; Ovis aries COX-1 crystallized with Alpha-Methyl-4-Biphenylacetic, resolution 2.00 Å) and COX-2 (pdb code: 3NT1; Mus musculus COX-2 crystallized with naproxen, resolution 1.73 Å) isozymes have paved the way for computational modeling. In the present work, from receptor cavities of enzyme, suitable scaffolds for both isozyme are generated by using ZINCv12 fragment library. Accelrys 3.1's Discovery Studio Protocols and de novo design module were assigned in the derivation process of the scaffolds via link library to produce 1129 analogs. GOLD and AutoDock 4 are used to scan and define poses in catalytic sites of both COX isozymes. Known inhibitors were taken as a reference for verification of modeling studies. The best resultant inhibitors are subjected to ADMET test and validity is confirmed.
Citation - WoS: 17
Citation - Scopus: 20
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.
In silico designing of isoform-selective inhibitors against class IIA histone deacetylases
(Kadir Has Üniversitesi, 2021) Elmezayen, Ammar Dawoud Ahmed Mahmoud; Yelekçi, Kemal
The fundamental cause of human cancer is strongly influenced by down- or upregulations of epigenetic factors. Upregulated histone deacetylases (HDAC) have been shown to be effectively neutralized by the action of HDACs inhibitors (HDACi). However, cytotoxicity has been reported in normal cells because of non-specificity of several available HDACis that are in clinical use or at different phases of clinical trials. Constant Search for specific HDAC isoform inhibitors is increasingly developing to avoid this side effect. Because of the high amino acid sequence and structural similarity among HDAC enzymes, it is believed to be a challenging task to obtain isoform-selectivity. The essential aim of the present study was to examine the similarity of class IIa HDACs (4, 5, 7, and 9) by aligning their structures and amino acid sequences, active site extraction, and recognition of the key amino acid residues within the catalytic channel. X-ray crystal structure of the human HDAC4 was used as a template for homology modeling of human HDACs 5 and 9. Consequently, isoform-selective inhibitors against class IIa HDACs were identified via structure- and ligand-based drug design. Based on the highest binding affinity and isoform-selectivity, the top-ranked inhibitors were in silico tested for their absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties, which were classified as drug-like compounds. Later, molecular dynamics simulation (MD) was carried out for all compound-protein complexes to evaluate the structural stability and the biding mode of the inhibitors, which showed high stability throughout the 100 ns simulation. Free binding energy predictions by MM-PBSA method showed the high binding affinity of the identified compounds towards their respective targets. Hence, these inhibitors could be used as drug candidates or as lead compounds for more in silico or in vitro optimization to design safe isoform-selective HDACs inhibitors.
In Silico Identification of Physiological Substrates and Inhibitors of Serum Paraoxonase 1 Enzyme
(Kadir Has Üniversitesi, 2014) Karabıyık, Talha; Yelekçi, Kemal
Paraoxonase 1 (PON1) as an important antioxidant enzyme against oxidative stress has been implicated in the pathogenesis of a number of disorders including cancer cardiovascular and several other diseases. Although there has been considerable progress in understanding the PON1 enzyme its precise physiological substrate and function still remain inconclusive. Discovery of new PON1 substrates or inhibitors will provide better understanding of PON1’s cardiovascular protective and antioxidant effects. PON1 is known to show lactonase aryl esterase and phosphotriesterase (paraoxonase) activity. PON1 having two calcium ions within its central tunnel shows six-bladed ?-propeller with each arm comprising of four ?-sheets. The structural Ca2+ is buried whereas the catalytic Ca2+ lies at the bottom of the activesite cavity. in this study metabolites of Human Metabolome Database (HMDB) version 3.0 containing over 40000 metabolites were docked against the PON1 structure (PDB iD: 3SRE) determined by Ben-David et al. in a virtual screening scenario using AutoDock 4.2 and metabolites were evaluated in terms of docking energy and docking pose. The best 2000 metabolites in terms of docking energy were inspected one by one and 97 of them were selected due to their chemical groups that the PON1 may work on. These 97 metabolites were further evaluated in terms of their docking poses and this further evaluation revealed that 10 out of 97 had the correct docking pose. These aforementioned metabolites are sorgolactone indoxyl sulfate 5- methoxyhinokinin enterolactone (-)-arctigenin epoxybergamottin pandamarilactone 32 (-)-matairesinol alectrol isoalantolactone. Except indoxyl sulfate all of them are of plant origin. it is known that PON1 activity is negatively correlated with high intake of vegetables. With this data and docking energies of metabolites of plant origin mentioned above in hand it is suggested that these metabolites of plant origin may be PON1 inhibitors. indoxyl sulfate plays roles in mechanisms of various diseases and causes oxidative stress. This metabolite also has considerably low docking energy and may also be a PON1 inhibitor. To be certain about the PON1 inhibitory potential of these mentioned 10 metabolites laboratory assays should be carried out. -- Abstract'tan.
In Silico Screening of Neuronal Nitric Oxide Synthase Enzyme Inhibitors
(Kadir Has Üniversitesi, 2014) Örtmen, Bahanur; Yelekçi, Kemal
Three closely related isoforms of nitric oxide synthases (NOS) catalyze an important secondary messenger nitric oxide (NO) synthesis through oxidation of L-arginine to L-citrulline. These three NOS isoforms takes parts in different tissues for various physiological and pathological processes. Neuronal NOS (nNOS) produce NO in central and peripheral nervous system endothelial NOS (eNOS) plays role in endothelial cells and NO in macrophage cells is produced by inducible NOS (iNOS). Excessive NO production in nervous cells following pathological conditions is observed. Dysregulation of NO therefore may force NO to act as a neurotoxin that causes several neurodegenerative diseases including Parkinson’s Alzheimer’s Huntington’s diseases. Considering all these facts developing a selective and good potential inhibitor for nNOS is a compulsory task to achieve. However among all APPE isoforms there is high active site conservation so that no drug that shows these desired properties has yet been designed and developed.in this present work virtual screening techniques were applied to design selective nNOS inhibitors. Molecular modeling studies were done using already known crystal structures of all three isoforms. First of all to find primary lead candidates several hundred compounds were screened via ZiNCv12 lead library. Then modifications were done on the selected scaffolds via de novo design method to derive our inhibitor candidates. AutoDock 4.02 docking virtual tool was employed for docking and scoring of inhibitor candidates. inhibition constants and best pose predictions of docked ligands within the active sites of three isoforms were considered for further examinations and comparison analysis. Already bound ligands in downloaded experimentally determined X-ray structures of all isoforms were re-docked to crosscheck our studies. in this thesis two lead scaffolds among all and 22 inhibitor candidates derived from these two scaffolds were selected to discuss for optimization for further development of best potential and selective inhibitor for nNOS. -- Abstract'tan.
In Silico Screening of Potent Histon Demethylase1 (lsd1) Enzyme Inhibitor
(Kadir Has Üniversitesi, 2020) TAHER AL-RIKABI, MARYAM MUHSIN; Yelekçi, Kemal
Histone lysine specific demethylase (LSD1) is one of the main enzymes which regulates histone demethylation which in return regulates different epigenetic processes such DNA replication and transcription also gene silencing. Moreover, recent studies have made a direct yet unclear link between LSD1 and the development of several diseases such viral infections, neurodegenerative diseases and most commonly cancer. An overexpression of the enzyme has been observed in different types of cancer including; acute myeloid leukemia (AML), breast cancer, lung cancer and prostate cancer. This observation led to the development of two LSD1 inhibitors; Tranylcypromine and 2-[4-methoxy-phenyl] Cyclopropylamine yet both have demonstrated low selectivity against the enzyme therefore this study along with many others solo focus on finding more potent LSD1 inhibitors through applying newly developed computer aided drug design (in silico) approaches. In this study Zinc15 database was screened in order to obtain pre-synthesized potential lead compounds. 40 thousand compounds were obtained, prepared and docked in two phases, firstly with PyRx autodock vina software and afterwards the compounds that have passed the first evaluation were further docked in autodock4 software and a total of 24 compounds have shown potential with a binding energy of -8.00 kcal/mol and less. Later on, Discovery Studio Visualizer software was used to generate 2D and 3D diagram pictures of the enzyme – ligand complex to further display and investigate the ligand interactions in the enzymes binding pocket.
In Silico Screening of Potent Hiv-1 Integrase Inhibitors for the Treatment of Human Immunodeficiency Virus (hiv)
(Kadir Has Üniversitesi, 2018) Samorlu, Augustine; Yelekçi, Kemal
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.