Araştırma Çıktıları | WoS | Scopus | TR-Dizin | PubMed
Permanent URI for this communityhttps://hdl.handle.net/20.500.14719/1741
Browse
52 results
Search Results
Publication Metadata only Molecular insights into the AT1 antagonism based on biophysical and in silico studies of telmisartan(2013) Kritsi, Eftichia; Potamitis, Constantinos; Durdagi, Serdar; Zoumpoulakis, Panagiotis G.; Golič-Grdadolnik, Simona; Mavromoustakos, Thomas M.; Kritsi, Eftichia, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece; Potamitis, Constantinos, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Zoumpoulakis, Panagiotis G., Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Golič-Grdadolnik, Simona, Laboratory of Biomolecular Structure, National Institute of Chemistry Ljubljana, Ljubljana, Slovenia, EN-FIST Centre of Excellence, Ljubljana, Slovenia; Mavromoustakos, Thomas M., Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece, Department of Chemistry, National and Kapodistrian University of Athens, Athens, GreeceAT1 antagonists (SARTANs) constitute one of the most successful classes of antihypertensive agents. These molecules interfere with the renin angiotensin system by preventing the vasoconstrictive hormone angiotensin II from binding onto the AT1 receptor. It is proposed that SARTANs exert their biological action by inserting into the lipid membrane and then diffuse to the active site of AT1 receptor. In this article, the conformational properties of telmisartan are analyzed both in solution and in the active site of the AT1 receptor using conformational analysis, molecular docking, Molecular Dynamics (MD) simulations, and in silico Ala-scanning mutagenesis studies. Combined results reveal telmisartan's crucial structural characteristics and classify the importance of receptor's amino acids for ligand binding. Since telmisartan is exerting its activity on a transmembrane receptor, Differential Scanning Calorimetry was applied to study the drug effects in lipid bilayers mimicking the biological membrane environment. Of paramount importance, is the finding that telmisartan exerted similarities but also significant differences with other AT1 antagonists on the basis of their interaction with lipid bilayers and subsequent docking into the active site. This could in part explain their similar mode of action and in parallel their distinct pharmacological profile. © 2013 Springer Science+Business Media New York. © 2013 Elsevier B.V., All rights reserved.Publication Metadata only Designing of multi-targeted molecules using combination of molecular screening and in silico drug cardiotoxicity prediction approaches(Elsevier Inc. usjcs@elsevier.com, 2014) Buturak, Birce; Durdagi, Serdar; Noskov, Sergei Yu; Ildeniz, A. Tugba Ozal; Buturak, Birce, Graduate School of Science and Engineering, Kadir Has Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Noskov, Sergei Yu, Institute for Biocomplexity and Informatics, University of Calgary, Calgary, Canada; Ildeniz, A. Tugba Ozal, Graduate School of Science and Engineering, Kadir Has Üniversitesi, Istanbul, Turkey, Department of Bioinformatics and Genetics, Kadir Has Üniversitesi, Istanbul, TurkeyWe have previously investigated and reported a set of phenol- and indole-based derivatives at the binding pockets of carbonic anhydrase isoenzymes using in silico and in vitro analyses. In this study, we extended our analysis to explore multi-targeted molecules from this set of compounds. Thus, 26 ligands are screened at the binding sites of 229 proteins from 5 main enzyme family classes using molecular docking algorithms. Derived docking scores are compared with reported results of ligands at carbonic anhydrase I and II isoenzymes. Results showed potency of multi-targeted drugs of a few compounds from investigated ligand set. These promising ligands are then tested in silico for their cardiotoxicity risks. Results of this work can be used to improve the desired effects of these compounds by molecular engineering studies. In addition these results may lead to further investigation of studied molecules by medicinal chemists to explore different therapeutic aims. © 2014 Elsevier Inc. © 2014 Elsevier B.V., All rights reserved.Publication Metadata only Inhibition of mammalian carbonic anhydrases I-XIV with grayanotoxin III: Solution and in silico studies(Informa Healthcare healthcare.enquiries@informa.com, 2014) Durdagi, Serdar; Scozzafava, Gabriele; Vullo, Daniela; Şahin, Hüseyin; Kolaylı, Sevgi; Supuran, Claudiu T.; Durdagi, Serdar, Institute for Biocomplexity and Informatics, University of Calgary, Calgary, Canada, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Scozzafava, Gabriele, Dipartimento di Economia, Università degli Studi di Firenze, Florence, Italy; Vullo, Daniela, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Florence, Italy; Şahin, Hüseyin, Department of Chemistry, Karadeniz Technical University, Trabzon, Turkey; Kolaylı, Sevgi, Department of Chemistry, Karadeniz Technical University, Trabzon, Turkey; Supuran, Claudiu T., Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Florence, Italy, NEUROFARBA Department, Università degli Studi di Firenze, Florence, ItalyGrayanotoxin III (GTX3) was investigated for inhibition of all catalytically active mammalian carbonic anhydrase (CA, EC 4.2.1.1) isoforms, i.e. CA I to CA XIV. It showed micromolar inhibition (KIs of 8.01 and 6.13μM) for cytosolic isoforms CA I and II, respectively. GTX3 showed a submicromolar inhibition (KIs in the range of 0.51-2.15μM) for the remaining cytosolic (CA III, VII and XIII), membrane-associated/transmembrane (CA IV, IX, XII and XIV), mitochondrial (CA VA and CA VB) and secreted (CA VI) isoforms. This inhibition profile is very different from that of the sulfonamide CA inhibitors (CAIs), which possess different clinical applications. A molecular docking study for GTX3 within the active sites of CA I and II assisted to the understanding of molecular mechanism of the ligand. The interesting inhibition profile, coupled with various possibilities of interacting with the enzyme active site make this family of natural compounds attractive leads for designing novel chemotypes acting as CAIs. © 2014 Informa UK Ltd. © 2015 Elsevier B.V., All rights reserved.Publication Metadata only Carbonic anhydrase inhibitory properties of novel benzylsulfamides using molecular modeling and experimental studies(Academic Press Inc. apjcs@harcourt.com, 2014) Göksu, Süleyman; Naderi, Ali; Akbaba, Yusuf; Kalın, Pınar; Akıncıoğlu, Akın; Gülçın, İlhami; Durdagi, Serdar; Salmas, Ramin Ekhteiari; Göksu, Süleyman, Department of Chemistry, Atatürk Üniversitesi, Erzurum, Turkey; Naderi, Ali, Department of Chemistry, Atatürk Üniversitesi, Erzurum, Turkey; Akbaba, Yusuf, Department of Basic Sciences, Erzurum Technical University, Erzurum, Turkey; Kalın, Pınar, Department of Chemistry, Atatürk Üniversitesi, Erzurum, Turkey; Akıncıoğlu, Akın, Central Research and Application Laboratory, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey; Gülçın, İlhami, Department of Chemistry, Atatürk Üniversitesi, Erzurum, Turkey, Department of Zoology, College of Sciences, Riyadh, Saudi Arabia; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Salmas, Ramin Ekhteiari, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, TurkeyIn this study, a series of sulfamoyl carbamates and sulfamide derivatives were synthesized. Six commercially available benzyl amines and BnOH were reacted with chlorosulfonyl isocyanate (CSI) to give sulfamoyl carbamates. Pd-C catalyzed hydrogenolysis reactions of carbamates afforded sulfamides. The inhibition effects of novel benzylsulfamides on the carbonic anhydrase I, and II isoenzymes (CA I, and CA II) purified from fresh human blood red cells were determined by Sepharose-4B-L-Tyrosine-sulfanilamide affinity chromatography. In vitro studies were shown that all of novel synthesized benzylsulfamide analogs inhibited, concentration dependently, both hCA isoenzyme activities. The novel benzylsulfamide compounds investigated here exhibited nanomolar inhibition constants against the two isoenzymes. Ki values were in the range of 28.48 ± 0.01-837.09 ± 0.19 nM and 112.01 ± 0.01-268.01 ± 0.22 nM for hCAI and hCA II isoenzymes, respectively. Molecular modeling approaches were also applied for studied compounds. © 2014 Elsevier Inc. All rights reserved. © 2014 Elsevier B.V., All rights reserved.Publication Metadata only Discovery of potent carbonic anhydrase and acetylcholine esterase inhibitors: Novel sulfamoylcarbamates and sulfamides derived from acetophenones(Elsevier Ltd, 2015) Akıncıoğlu, Akın; Akincioʇlu, Hülya; Gülçın, İlhami; Durdagi, Serdar; Supuran, Claudiu T.; Göksu, Süleyman; Akıncıoğlu, Akın, Central Research and Application Laboratory, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey, Department of Chemistry, Atatürk Üniversitesi, Erzurum, Turkey; Akincioʇlu, Hülya, Central Research and Application Laboratory, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey, Department of Chemistry, Atatürk Üniversitesi, Erzurum, Turkey; Gülçın, İlhami, Department of Chemistry, Atatürk Üniversitesi, Erzurum, Turkey, Department of Zoology, College of Sciences, Riyadh, Saudi Arabia; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Supuran, Claudiu T., NEUROFARBA Department, Università degli Studi di Firenze, Florence, Italy; Göksu, Süleyman, Department of Chemistry, Atatürk Üniversitesi, Erzurum, TurkeyAbstract In this study, several novel sulfamides were synthesized and evaluated for their acetylcholine esterase (AChE) and human carbonic anhydrase I, and II isoenzymes (hCA I and II) inhibition profiles. Reductive amination of methoxyacetophenones was used for the synthesis of amines. Amines were converted to sulfamoylcarbamates with chlorosulfonyl isocyanate (CSI) in the presence of BnOH. Pd-C catalyzed hydrogenolysis of sulfamoylcarbamates afforded sulfamides. These novel compounds were good inhibitors of the cytosolic hCA I, and hCA II with Ki values in the range of 45.9 ± 8.9-687.5 ± 84.3 pM for hCA I, and 48.80 ± 8.2-672.2 ± 71.9 pM for hCA II. The inhibitory effects of the synthesized novel compounds on AChE were also investigated. The Ki values of these compounds were in the range of 4.52 ± 0.61-38.28 ± 6.84 pM for AChE. These results show that hCA I, II, and AChE were effectively inhibited by the novel sulfamoylcarbamates 17-21 and sulfamide derivatives 22-26. All investigated compounds were docked within the active sites of the corresponding enzymes revealing the reasons of the effective inhibitory activity. © 2015 Elsevier B.V., All rights reserved.Publication Metadata only Interaction of carbonic anhydrase isozymes I, II, and IX with some pyridine and phenol hydrazinecarbothioamide derivatives(Elsevier Ltd, 2015) Işik, Semra; Vullo, Daniela; Durdagi, Serdar; Ekinci, Deniz; Şentürk, Murat; Cetin, Ahmet; Şentürk, Esra; Supuran, Claudiu T.; Işik, Semra, Department of Chemistry, Balikesir Üniversitesi, Balikesir, Turkey; Vullo, Daniela, NEUROFARBA Department, Università degli Studi di Firenze, Florence, Italy; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Ekinci, Deniz, Department of Agricultural Biotechnology, Ondokuz Mayis Üniversitesi, Samsun, Turkey; Şentürk, Murat, Department of Chemistry, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey; Cetin, Ahmet, Department of Chemistry, Bingöl Üniversitesi, Bingol, Turkey; Şentürk, Esra, School of Heatlh Services, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey; Supuran, Claudiu T., NEUROFARBA Department, Università degli Studi di Firenze, Florence, ItalyA series of hydrazinecarbothioamide derivatives incorporating ethyl, phenyl, tolyl, benzyl, and allyl moieties were prepared and tested as possible inhibitors of three members of the pH regulatory enzyme family, carbonic anhydrase (CA, EC 4.2.1.1). The inhibitory and activatory potencies of the compounds against the cytosolic human isoforms hCA I and hCA II and the transmembrane, tumor-associated hCA IX were analyzed by a hydrase assay with CO2 as substrate, and the inhibition constants (KI) were calculated. Most compounds investigated here exhibited nanomolar or low micromolar inhibition constants against the three isoenzymes. KI values were in the range of 34.1-871 nM for hCA I and compounds 5-10 showed interesting activation of the hCA II with KA value of 0.81-12.5 μM. Compounds 11-16 exhibited moderate inhibition effects on hCA IX in the range of 0.317-1.245 μM but they were less effective for hCA II. Tested compounds were also investigated using in silico applications at the binding pockets of these three targets. The different mechanisms of inhibition by these tested compounds as compared to sulfonamides, and their diverse inhibition profile for these mammalian isozymes, makes this class of derivatives of great interest for the design of novel CA inhibitors. © 2017 Elsevier B.V., All rights reserved.Publication Metadata only Carbonic anhydrase inhibitors: Design, synthesis, kinetic, docking and molecular dynamics analysis of novel glycine and phenylalanine sulfonamide derivatives(Elsevier Ltd, 2015) Fidan, Ismail; Salmas, Ramin Ekhteiari; Arslan, Mehmet; Şentürk, Murat; Durdagi, Serdar; Ekinci, Deniz; Şentürk, Esra; Coşgun, Sedat; Supuran, Claudiu T.; Fidan, Ismail, Department of Chemistry, Gebze Teknik Üniversitesi, Gebze, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Arslan, Mehmet, Department of Polymer Materials Engineering, Yalova Üniversitesi, Yalova, Turkey; Şentürk, Murat, Department of Chemistry, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Ekinci, Deniz, Department of Agricultural Biotechnology, Ondokuz Mayis Üniversitesi, Samsun, Turkey; Şentürk, Esra, School of Health Services, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey; Coşgun, Sedat, Department of Chemistry, Fatih Üniversitesi, Istanbul, Turkey; Supuran, Claudiu T., NEUROFARBA Department, Università degli Studi di Firenze, Florence, ItalyThe inhibition of two human cytosolic carbonic anhydrase isozymes I and II, with some novel glycine and phenylalanine sulfonamide derivatives were investigated. Newly synthesized compounds G1-4 and P1-4 showed effective inhibition profiles with KI values in the range of 14.66-315 μM for hCA I and of 18.31-143.8 μM against hCA II, respectively. In order to investigate the binding mechanisms of these inhibitors, in silico docking studies were applied. Atomistic molecular dynamic simulations were performed for docking poses which utilize to illustrate the inhibition mechanism of used inhibitors into active site of CAII. These sulfonamide containing compounds generally were competitive inhibitors with 4-nitrophenylacetate as substrate. Some investigated compounds here showed effective hCA II inhibitory effects, in the same range as the clinically used sulfonamide, sulfanilamide or mafenide and might be used as leads for generating enzyme inhibitors possibly targeting other CA isoforms which have not been yet assayed for their interactions with such agents. © 2015 Elsevier B.V., All rights reserved.Publication Metadata only Fullerene-based inhibitors of HIV-1 protease(John Wiley and Sons Ltd Southern Gate Chichester, West Sussex PO19 8SQ, 2015) Strom, T. Amanda; Durdagi, Serdar; Ersoz, Suha Salih; Salmas, Ramin Ekhteiari; Supuran, Claudiu T.; Barron, Andrew Ross; Strom, T. Amanda, Department of Chemistry, Rice University, Houston, United States; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Biological Sciences, University of Calgary, Calgary, Canada; Ersoz, Suha Salih, School of Medicine, Bahçeşehir Üniversitesi, Istanbul, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Supuran, Claudiu T., Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Florence, Italy; Barron, Andrew Ross, Department of Chemistry, Rice University, Houston, United States, George R. Brown School of Engineering and Computing, Houston, United States, Institute of Life Science, Swansea University, Swansea, United KingdomA series of Fmoc-Phe(4-aza-C60)-OH of fullerene amino acid derived peptides have been prepared by solid phase peptide synthesis, in which the terminal amino acid, Phe(4-aza-C60)-OH, is derived from the dipolar addition to C60 of the Fmoc-Nα-protected azido amino acids derived from phenylalanine: Fmoc-Phe(4-aza-C60)-Lys3-OH (1), Fmoc-Phe(4-aza-C60)-Pro-Hyp-Lys-OH (2), and Fmoc-Phe(4-aza-C60)-Hyp-Hyp-Lys-OH (3). The inhibition constant of our fullerene aspartic protease PRIs utilized FRET-based assay to evaluate the enzyme kinetics of HIV-1 PR at various concentrations of inhibitors. Simulation of the docking of the peptide Fmoc-Phe-Pro-Hyp-Lys-OH overestimated the inhibition, while the amino acid PRIs were well estimated. The experimental results show that C60-based amino acids are a good base structure in the design of protease inhibitors and that their inhibition can be improved upon by the addition of designer peptide sequences. © 2017 Elsevier B.V., All rights reserved.Publication Metadata only Leveraging NMR and X-ray data of the free ligands to build better drugs targeting angiotensin II Type 1 G-Protein coupled receptor(Bentham Science Publishers P.O. Box 294 Bussum 1400 AG, 2016) Kellici, Tahsin F.; Ntountaniotis, Dimitrios; Kritsi, Eftichia; Zervou, Maria V.; Zoumpoulakis, Panagiotis G.; Potamitis, Constantinos; Durdagi, Serdar; Salmas, Ramin Ekhteiari; Ergun, Gizem; Gokdemir, Ebru; Kellici, Tahsin F., Department of Chemistry, University of Ioannina, Ioannina, Greece, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece; Ntountaniotis, Dimitrios, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece; Kritsi, Eftichia, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Zervou, Maria V., Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Zoumpoulakis, Panagiotis G., Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Potamitis, Constantinos, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Ergun, Gizem, School of Medicine, Bahçeşehir Üniversitesi, Istanbul, Turkey; Gokdemir, Ebru, School of Medicine, Bahçeşehir Üniversitesi, Istanbul, TurkeyThe angiotensin II type 1 receptor (AT1R) has been recently crystallized. A new era has emerged for the structure-based rational drug design and the synthesis of novel AT1R antagonists. In this critical review, the X-ray crystallographic data of commercially available AT1R antagonists in free form are analyzed and compared with the conformational analysis results obtained using a combination of NMR spectroscopy and Molecular Modeling. The same AT1R antagonists are docked and compared in terms of their interactions in their binding site using homology models and the crystallized AT1R receptor. Various aspects derived from these comparisons regarding rational drug design are outlined. © 2020 Elsevier B.V., All rights reserved.Publication Metadata only In silico investigation of PARP-1 catalytic domains in holo and apo states for the design of high-affinity PARP-1 inhibitors(Taylor and Francis Ltd healthcare.enquiries@informa.com, 2016) Salmas, Ramin Ekhteiari; Ünlü, Ayhan; Yurtsever, Mine; Noskov, Sergei Yu; Durdagi, Serdar; Salmas, Ramin Ekhteiari, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Ünlü, Ayhan, Department of Biophysics, Trakya Üniversitesi, Edirne, Turkey; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Noskov, Sergei Yu, Department of Biological Sciences, University of Calgary, Calgary, Canada; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyThe rational design of high-affinity inhibitors of poly-ADP-ribose polymerase-1 (PARP-1) is at the heart of modern anti-cancer drug design. While relevance of enzyme to DNA repair processes in cellular environment is firmly established, the structural and functional understanding of the main determinants for high-affinity ligands controlling PARP-1 activity is still lacking. The conserved active site of PARP-1 represents an ideal target for inhibitors and may offer a novel target at the treatment of breast cancer. To fill the gap in the structural knowledge, we report on the combination of molecular dynamics (MD) simulations, principal component analysis (PCA), and conformational analysis that analyzes in great details novel binding mode for a number of inhibitors at the PARP-1. While optimization of the binding affinity for original target is an important goal in the drug design, many of the promising molecules for treatment of the breast cancer are plagued by significant cardiotoxicity. One of the most common side-effects reported for a number of polymerase inhibitors is its off-target interactions with cardiac ion channels and hERG1 channel, in particular. Thus, selected candidate PARP-1 inhibitors were also screened in silico at the central cavities of hERG1 potassium ion channel. © 2018 Elsevier B.V., All rights reserved.