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Publication Metadata only AT1 antagonists: A patent review (2008 - 2012)(2013) Mavromoustakos, Thomas M.; Agelis, George; Durdagi, Serdar; Mavromoustakos, Thomas M., Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece; Agelis, George, Department of Chemistry, University of Patras, Rio, Greece, Eldrug S.A., Patra, Greece; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyIntroduction: For two decades a class of pharmaceutical molecules with proved beneficial therapeutic properties, especially in hypertension, has been introduced in the market aiming to specifically prevent the detrimental effects of the peptide hormone Angiotensin II at the AT1 receptor. The prototype of this class was losartan and based on its structure, several drugs were launched and also called 'Sartans'. New structural features on these molecules can provide multi-target properties in the RAS or other systems. New methodologies were developed for the treatment of hypertension utilizing either AT1 antagonists alone or as cocktails. Areas covered: In this review article, authors aim to cover information provided by patents of the years 2008-2012. The rationale of writing this review article is to cover the most important patents which can forward the field with new important discoveries. Expert opinion: From the patent investigation it is clear that new areas on the subject are still offered for new discoveries. New structural features can be still considered in the synthetic compounds that can advance the knowledge and beneficial effects on diseases related to Angiotensin II and AT1 receptor. There is era also for new formulations (i.e., cyclodextrins, polymers and liposomes). The multitarget approach can be further strengthened and more combinations can be sought in the rational drug design for seeking cocktails. Furthermore, the revealing of the complexity of the RAS offers new avenues for novel targets and this must not be overlooked. © 2013 Informa UK, Ltd. © 2013 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 Elucidation of conformational states, dynamics, and mechanism of binding in human κ-opioid receptor complexes(American Chemical Society, 2014) Leonis, Georgios; Avramopoulos, Aggelos; Salmas, Ramin Ekhteiari; Durdagi, Serdar; Yurtsever, Mine; Papadopoulos, Manthos G.; Leonis, Georgios, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Avramopoulos, Aggelos, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Salmas, Ramin Ekhteiari, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Papadopoulos, Manthos G., Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, GreeceOpioid G protein-coupled receptors (GPCRs) have been implicated in modulating pain, addiction, psychotomimesis, mood and memory, among other functions. We have employed the recently reported crystal structure of the human κ-opioid receptor (κ-OR) and performed molecular dynamics (MD), free energy, and ab initio calculations to elucidate the binding mechanism in complexes with antagonist JDTic and agonist SalA. The two systems were modeled in water and in DPPC lipid bilayers, in order to investigate the effect of the membrane upon conformational dynamics. MD and Atoms in Molecules (AIM) ab initio calculations for the complexes in water showed that each ligand was stabilized inside the binding site of the receptor through hydrogen bond interactions that involved residues Asp138 (with JDTic) and Gln115, His291, Leu212 (with SalA). The static description offered by the crystal structure was overcome to reveal a structural rearrangement of the binding pocket, which facilitated additional interactions between JDTic and Glu209/Tyr139. The role of Glu209 was emphasized, since it belongs to an extracellular loop that covers the binding site of the receptor and is crucial for ligand entrapment. The above interactions were retained in membrane complexes (SalA forms additional hydrogen bonds with Tyr139/312), except the Tyr139 interaction, which is abolished in the JDTic complex. For the first time, we report that JDTic alternates between a V-shape (stabilized via a water-mediated intramolecular interaction) and a more extended conformation, a feature that offers enough suppleness for effective binding. Moreover, MM-PBSA calculations showed that the more efficient JDTic binding to κ-OR compared to SalA (ΔGJDTic = -31.6 kcal mol-1, ΔGSalA = -9.8 kcal mol-1) is attributed mostly to differences in electrostatic contributions. Importantly, our results are in qualitative agreement with the experiments (ΔG JDTic,exp = -14.4 kcal mol-1, ΔGSalA,exp = -10.8 kcal mol-1). This study provides previously unattainable information on the dynamics of human κ-OR and insight on the rational design of drugs with improved pharmacological properties. © 2014 American Chemical Society. © 2022 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 Modeling and protein engineering studies of active and inactive states of human dopamine D2 receptor (D2R) and investigation of drug/receptor interactions(Kluwer Academic Publishers, 2015) Salmas, Ramin Ekhteiari; Yurtsever, Mine; Stein, Matthias Jeanette; Durdagi, Serdar; Salmas, Ramin Ekhteiari, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Stein, Matthias Jeanette, Molecular Simulations and Design Group, Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany; Durdagi, Serdar, Molecular Simulations and Design Group, Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyHomology model structures of the dopamine D2 receptor (D2R) were generated starting from the active and inactive states of β2-adrenergic crystal structure templates. To the best of our knowledge, the active conformation of D2R was modeled for the first time in this study. The homology models are built and refined using MODELLER and ROSETTA programs. Top-ranked models have been validated with ligand docking simulations and in silico Alanine-scanning mutagenesis studies. The derived extra-cellular loop region of the protein models is directed toward the binding site cavity which is often involved in ligand binding. The binding sites of protein models were refined using induced fit docking to enable the side-chain refinement during ligand docking simulations. The derived models were then tested using molecular modeling techniques on several marketed drugs for schizophrenia. Alanine-scanning mutagenesis and molecular docking studies gave similar results for marketed drugs tested. We believe that these new D2 receptor models will be very useful for a better understanding of the mechanisms of action of drugs to be targeted to the binding sites of D2Rs and they will contribute significantly to drug design studies involving G-protein-coupled receptors in the future. © 2016 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 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.