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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 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.Publication Metadata only Kinetic and in silico studies of hydroxy-based inhibitors of carbonic anhydrase isoforms I and II(Taylor and Francis Ltd healthcare.enquiries@informa.com, 2016) Salmas, Ramin Ekhteiari; Mestanoglu, Mert; Durdagi, Serdar; Şentürk, Murat; Kaya, Afşin Ahmet; Kaya, Elif Çelenk; Salmas, Ramin Ekhteiari, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Mestanoglu, Mert, School of Medicine, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Şentürk, Murat, Department of Chemistry, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey; Kaya, Afşin Ahmet, School of Health, Gümüşhane Üniversitesi, Gumushane, Turkey; Kaya, Elif Çelenk, School of Health, Gümüşhane Üniversitesi, Gumushane, TurkeyA series of hydroxy and phenolic compounds have been assayed for the inhibition of two physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic human isozymes I and II. The investigated molecules showed inhibition constants in the range of 1.07-4003 and 0.09-31.5 μM at the hCA I and hCA II enzymes, respectively. In order to investigate the binding mechanisms of these inhibitors, in silico studies were also applied. Molecular docking scores of the studied compounds are compared using three different scoring algorithms, namely Glide/SP, Glide/XP and Glide/IFD. In addition, different ADME (absorption, distribution, metabolism and excretion) analysis was performed. All the examined compounds were found within the acceptable range of pharmacokinetic profiles. © 2016 Elsevier B.V., All rights reserved.Publication Metadata only Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques(American Chemical Society service@acs.org, 2016) Durdagi, Serdar; Salmas, Ramin Ekhteiari; Stein, Matthias Jeanette; Yurtsever, Mine; Seeman, Philip; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, 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; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Seeman, Philip, Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, CanadaWe have recently reported G-protein coupled receptor (GPCR) model structures for the active and inactive states of the human dopamine D2 receptor (D2R) using adrenergic crystal structures as templates. Since the therapeutic concentrations of dopamine agonists that suppress the release of prolactin are the same as those that act at the high-affinity state of the D2 receptor (D2High), D2High in the anterior pituitary gland is considered to be the functional state of the receptor. In addition, the therapeutic concentrations of anti-Parkinson drugs are also related to the dissociation constants in the D2High form of the receptor. The discrimination between the high- And low-affinity (D2Low) components of the D2R is not obvious and requires advanced computer-assisted structural biology investigations. Therefore, in this work, the derived D2High and D2Low receptor models (GPCR monomer and dimer three-dimensional structures) are used as drug-binding targets to investigate binding interactions of dopamine and apomorphine. The study reveals a match between the experimental dissociation constants of dopamine and apomorphine at their high- And low-affinity sites of the D2 receptor in monomer and dimer and their calculated dissociation constants. The allosteric receptor-receptor interaction for dopamine D2R dimer is associated with the accessibility of adjacent residues of transmembrane region 4. The measured negative cooperativity between agonist ligand at dopamine D2 receptor is also correctly predicted using the D2R homodimerization model. © 2017 Elsevier B.V., All rights reserved.Publication Open Access Evaluation of the potential toxicity of unmodified and modified cyclodextrins on murine blood-brain barrier endothelial cells(Japanese Society of Toxicology, 2016) Shityakov, Sergey V.; Salmas, Ramin Ekhteiari; Salvador, Ellaine; Roewer, Norbert; Broscheit, Jens Albert; Förster, Carola Yvette; Shityakov, Sergey V., Department of Anesthesia and Critical Care, Julius-Maximilians-Universität Würzburg, Wurzburg, Germany; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Salvador, Ellaine, Department of Anesthesia and Critical Care, Julius-Maximilians-Universität Würzburg, Wurzburg, Germany; Roewer, Norbert, Department of Anesthesia and Critical Care, Julius-Maximilians-Universität Würzburg, Wurzburg, Germany; Broscheit, Jens Albert, Department of Anesthesia and Critical Care, Julius-Maximilians-Universität Würzburg, Wurzburg, Germany; Förster, Carola Yvette, Department of Anesthesia and Critical Care, Julius-Maximilians-Universität Würzburg, Wurzburg, GermanyIn this study, we investigated the cytotoxic effects of unmodified α-cyclodextrin (α-CD) and modified cyclodextrins, including trimethyl-β-cyclodextrin (TRIMEB) and hydroxypropyl-β-cyclodextrin (HPβCD), on immortalized murine microvascular endothelial (cEND) cells of the bloodbrain barrier (BBB). A CellTiter-Glo® viability test, performed on the cEND cells showed significant differences among the different cyclodextrins. After 24 hr of incubation, TRIMEB was the most cytotoxic, and HPβCD was non-toxic. α-CD and TRIMEB exhibited greater cytotoxicity in the Dulbecco’s modified Eagle’s medium than in heat-inactivated human serum indicating protective properties of the human serum. The predicted dynamic toxicity profiles (Td) for α-CD and TRIMEB indicated higher cytotoxicity for these cyclodextrins compared to the reference compound (dimethylsulfoxide). Molecular dynamics simulation of cholesterol binding to the CDs suggested that not just cholesterol but phospholipids extraction might be involved in the cytotoxicity. Overall, the results demonstrate that HPβCD has the potential to be used as a candidate for drug delivery vector development and signify a correlation between the in vitro cytotoxic effect and cholesterol binding of cyclodextrins. © 2022 Elsevier B.V., All rights reserved.Publication Metadata only Virtual screening of eighteen million compounds against dengue virus: Combined molecular docking and molecular dynamics simulations study(Elsevier Inc. usjcs@elsevier.com, 2016) Mirza, Shaher Bano; Salmas, Ramin Ekhteiari; Fatmi, Muhammad Qaiser; Durdagi, Serdar; Mirza, Shaher Bano, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Fatmi, Muhammad Qaiser, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyDengue virus is a major issue of tropical and sub-tropical regions. Dengue virus has been the cause behind the major alarming epidemics in the history with mass causalities from the decades. Unavailability of on-shelf drugs for the prevention of further proliferation of virus inside the human body results in immense number of deaths each year. This issue necessitates the design of novel anti-dengue drug. The protease enzyme pathway is the critical target for drug design due to its significance in the replication, survival and other cellular activities of dengue virus. Therefore, approximately eighteen million compounds from the ZINC database have been virtually screened against nonstructural protein 3 (NS3). The incremental construction algorithm of Glide docking program has been used with its features high throughput virtual screening (HTVS), standard precision (SP), extra precision (XP) and in combination of Prime module, induced fit docking (IFD) approach has also been applied. Five top-ranked compounds were then selected from the IFD results with better predicted binding energies with the catalytic triad residues (His51, Asp75, and Ser135) that may act as potential inhibitors for the underlying target protease enzyme. The top-ranked compounds ZINC95518765, ZINC44921800, ZINC71917414, ZINC39500661, ZINC36681949 have shown the predicted binding energies of -7.55, -7.36, -8.04, -8.41, -9.18 kcal/mol, respectively, forming binding interactions with three catalytically important amino acids. Top-docking poses of compounds are then used in molecular dynamics (MD) simulations. In computational studies, our proposed compounds confirm promising results against all the four serotypes of dengue virus, strengthening the opportunity of these compounds to work as potential on-shelf drugs against dengue virus. Further experimentation on the proposed compounds can result in development of strong inhibitors. © 2017 Elsevier B.V., All rights reserved.Publication Metadata only Discovering novel carbonic anhydrase type IX (CA IX) inhibitors from seven million compounds using virtual screening and in vitro analysis(Taylor and Francis Ltd healthcare.enquiries@informa.com, 2016) Salmas, Ramin Ekhteiari; Şentürk, Murat; Yurtsever, Mine; Durdagi, Serdar; Salmas, Ramin Ekhteiari, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Şentürk, Murat, Department of Chemistry, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyCarbonic anhydrase type IX (CA IX) enzyme is mostly over expressed in different cancer cell lines and tumor tissues. Potent CA IX inhibitors can be effective for adjusting the pH imbalance in tumor cells. In the present work, we represented the successful application of high throughput virtual screening (HTVS) of large dataset from ZINC database included of ∼7 million compounds to discover novel inhibitors of CA IX. HTVS and molecular docking were performed using consequence Glide/standard precision (SP), extra precision (XP) and induced fit docking (IFD) molecular docking protocols. For each compound, docking code calculates a set of low-energy poses and then exhaustively scans the binding pocket of the target with small compounds. Novel CA IX inhibitor candidates were suggested based on molecular modeling studies and a few of them were tested using in vitro analysis. These compounds were determined as good inhibitors against human CA IX target with Ki in the range of 0.85-1.58 M. In order to predict the pharmaceutical properties of the selected compounds, ADME (absorption, distribution, metabolism and excretion) analysis was also carried out. © 2017 Elsevier B.V., All rights reserved.