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Publication Metadata only Carbonic anhydrase inhibitory properties of novel benzylsulfamides using molecular modeling and experimental studies(Academic Press Inc. [email protected], 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 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 Open Access Investigation of inhibition mechanism of chemokine receptor CCR5 by micro-second molecular dynamics simulations(Nature Publishing Group Houndmills Basingstoke, Hampshire RG21 6XS, 2015) Salmas, Ramin Ekhteiari; Yurtsever, Mine; Durdağı, Serdar; Salmas, Ramin Ekhteiari, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyChemokine receptor 5 (CCR5) belongs to G protein coupled receptors (GPCRs) and plays an important role in treatment of human immunodeficiency virus (HIV) infection since HIV uses CCR5 protein as a co-receptor. Recently, the crystal structure of CCR5-bound complex with an approved anti-retroviral drug (maroviroc) was resolved. During the crystallization procedure, amino acid residues (i.e., Cys224, Arg225, Asn226 and Glu227) at the third intra-cellular loop were replaced by the rubredoxin for stability reasons. In the current study, we aimed to understand the impact of the incorporated rubredoxin on the conformations of TM domains of the target protein. For this reason, rubredoxin was deleted from the crystal structure and the missing amino acids were engineered. The resultant structure was subjected to long (μs) molecular dynamics (MD) simulations to shed light into the inhibitory mechanism. The derived model structure displayed a significant deviation in the cytoplasmic domain of TM5 and IC3 in the absence of rubredoxin. The principal component analyses (PCA) and MD trajectory analyses revealed important structural and dynamical differences at apo and holo forms of the CCR5. © 2015 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 [email protected], 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 [email protected], 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 [email protected], 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 Metadata only Virtual screening of eighteen million compounds against dengue virus: Combined molecular docking and molecular dynamics simulations study(Elsevier Inc. [email protected], 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.
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