Araştırma Çıktıları | WoS | Scopus | TR-Dizin | PubMed
Permanent URI for this communityhttps://hdl.handle.net/20.500.14719/1741
Browse
11 results
Search Results
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 Open Access Molecular Simulations of Solved Co-crystallized X-Ray Structures Identify Action Mechanisms of PDEδ Inhibitors(Biophysical Society, 2015) Salmas, Ramin Ekhteiari; Mestanoğlu, Mert; Yurtsever, Mine; Noskov, Sergei Yu; Durdağı, Serdar; Salmas, Ramin Ekhteiari, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Mestanoglu, Mert, School of Medicine, Bahçeşehir Üniversitesi, Istanbul, 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, TurkeyPDEδ is a small protein that binds and controls the trafficking of RAS subfamily proteins. Its inhibition protects initiation of RAS signaling, and it is one of the common targets considered for oncological drug development. In this study, we used solved x-ray structures of inhibitor-bound PDEδ targets to investigate mechanisms of action of six independent all-atom MD simulations. An analysis of atomic simulations combined with the molecular mechanic-Poisson-Boltzmann solvent accessible surface area/generalized Born solvent accessible surface area calculations led to the identification of action mechanisms for a panel of novel PDEδ inhibitors. To the best of our knowledge, this study is one of the first in silico investigations on co-crystallized PDEδ protein. A detailed atomic-scale understanding of the molecular mechanism of PDEδ inhibition may assist in the design of novel PDEδ inhibitors. One of the most common side effects for diverse small molecules/kinase inhibitors is their off-target interactions with cardiac ion channels and human-ether-a-go-go channel specifically. Thus, all of the studied PDEδ inhibitors are also screened in silico at the central cavities of hERG1 potassium channels. © 2018 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 Open Access Kinetic and docking studies of cytosolic/tumor-associated carbonic anhydrase isozymes I, II and IX with some hydroxylic compounds(Taylor and Francis Ltd [email protected], 2016) Durdagi, Serdar; Korkmaz, Neslihan; Işik, Semra; Vullo, Daniela; Astley, Demet K.; Ekinci, Deniz; Salmas, Ramin Ekhteiari; Şentürk, Murat; Supuran, Claudiu T.; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Korkmaz, Neslihan, Department of Chemistry, Ege Üniversitesi, Izmir, Turkey; Işik, Semra, Department of Chemistry, Balikesir Üniversitesi, Balikesir, Turkey; Vullo, Daniela, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Florence, Italy; Astley, Demet K., Department of Chemistry, Ege Üniversitesi, Izmir, Turkey; Ekinci, Deniz, Department of Agricultural Biotechnology, Ondokuz Mayis Üniversitesi, Samsun, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Şentürk, Murat, Department of Chemistry, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey; Supuran, Claudiu T., Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Florence, ItalyA series of hydroxylic compounds (1–10, NK-154 and NK-168) have been assayed for the inhibition of three physiologically relevant carbonic anhydrase isozymes, the cytosolic isozymes I, II and tumor-associated isozyme IX. The investigated compounds showed inhibition constants in the range of 0.068–4003, 0.012–9.9 and 0.025–115 μm at the hCA I, hCA II and hCA IX 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 calculated using scoring algorithms, namely Glide/induced fit docking. The inhibitory potencies of the novel compounds were analyzed at the human isoforms hCA I, hCA II and hCA IX as targets and the KI values were calculated. © 2017 Elsevier B.V., All rights reserved.Publication Open Access Mutated form (G52E) of inactive diphtheria toxin CRM197: molecular simulations clearly display effect of the mutation to NAD binding(Taylor and Francis Ltd. [email protected], 2016) Salmas, Ramin Ekhteiari; Mestanoglu, Mert; Ünlü, Ayhan; Yurtsever, Mine; Durdagi, Serdar; Salmas, Ramin Ekhteiari, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Mestanoglu, Mert, School of Medicine, Bahçeşehir Üniversitesi, Istanbul, Turkey; Ünlü, Ayhan, Department of Biophysics, Trakya Üniversitesi, Edirne, Turkey; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyMutated form (G52E) of diphtheria toxin (DT) CRM197 is an inactive and nontoxic enzyme. Here, we provided a molecular insight using comparative molecular dynamics (MD) simulations to clarify the influence of a single point mutation on overall protein and active-site loop. Post-processing MD analysis (i.e. stability, principal component analysis, hydrogen-bond occupancy, etc.) is carried out on both wild and mutated targets to investigate and to better understand the mechanistic differences of structural and dynamical properties on an atomic scale especially at nicotinamide adenine dinucleotide (NAD) binding site when a single mutation (G52E) happens at the DT. In addition, a docking simulation is performed for wild and mutated forms. The docking scoring analysis and docking poses results revealed that mutant form is not able to properly accommodate the NAD molecule. © 2018 Elsevier B.V., All rights reserved.Publication Metadata only Investigation of inhibition of human glucose 6-phosphate dehydrogenase by some 99mTc chelators by in silico and in vitro methods(Taylor and Francis Ltd [email protected], 2016) Şahin, Ali; Şentürk, Murat; Salmas, Ramin Ekhteiari; Durdagi, Serdar; Ayan, Arif Kursat; Karagölge, Ali; Mestanoglu, Mert; Şahin, Ali, Department of Nuclear Medicine, Ataturk University, Faculty of Medicine, Erzurum, Turkey; Şentürk, Murat, Department of Chemistry, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Ayan, Arif Kursat, Department of Nuclear Medicine, Ataturk University, Faculty of Medicine, Erzurum, Turkey; Karagölge, Ali, Department of Nuclear Medicine, Ataturk University, Faculty of Medicine, Erzurum, Turkey; Mestanoglu, Mert, School of Medicine, Bahçeşehir Üniversitesi, Istanbul, TurkeyThe inhibitory effects of methoxyisobutylisonitrile (MIBI), diethylene triamine pentaacetic acid (DTPA), dimercaptosuccinic acid (DMSA) and metilendifosfonat (MDP) on human erythrocyte glucose 6-phosphate dehydrogenase (hG6PD) activity were investigated. For this purpose, hG6PD was initially purified 557-fold at a yield of 51.43% using 2′,5′-adenosine diphosphate (ADP) sepharose 4B affinity gel chromatography. The in vitro effects of these chelators on hG6PD enzyme were studied. IC50 values of MIBI, DTPA, DMSA and MDP were 0.056, 0.172, 0.274 and 0.175 mM, of hG6PD, respectively. It was detected in in vitro studies that the hG6PD enzyme is inhibited due to these radiopharmaceutical chelators. In addition to in vitro studies, in order to better understand the molecular mechanism of studied compounds, combined in silico approaches, including molecular docking and molecular dynamics (MD), simulations were successfully performed. MD simulations shed light on inhibition mechanisms of the individual inhibitors into the ligand-binding pocket of hG6PD. Essential amino acids for binding are also investigated using per-residue interaction analysis studies. © 2017 Elsevier B.V., All rights reserved.Publication Open Access Synthesis, biological activity and multiscale molecular modeling studies for coumaryl-carboxamide derivatives as selective carbonic anhydrase IX inhibitors(Taylor and Francis Ltd [email protected], 2017) Zengin Kurt, Belma; Sönmez, Fatih; Durdagi, Serdar; Aksoydan, Busecan; Salmas, Ramin Ekhteiari; Angeli, Andrea; Küçükislamoǧlu, Mustafa; Supuran, Claudiu T.; Zengin Kurt, Belma, Department of Pharmaceutical Chemistry, Bezmiâlem Vakıf Üniversitesi, Istanbul, Turkey; Sönmez, Fatih, Department of Chemistry, Sakarya Üniversitesi, Serdivan, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Aksoydan, Busecan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Angeli, Andrea, Dipartimento Neurofarba, Università degli Studi di Firenze, Florence, Italy; Küçükislamoǧlu, Mustafa, Department of Chemistry, Sakarya Üniversitesi, Serdivan, Turkey; Supuran, Claudiu T., Dipartimento Neurofarba, Università degli Studi di Firenze, Florence, ItalyNew coumaryl-carboxamide derivatives with the thiourea moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and their inhibitory activity against the human carbonic anhydrase (hCA) isoforms hCA I, II, VII and IX were evaluated. While the hCA I, II and VII isoforms were not inhibited by the investigated compounds, the tumour-associated isoform hCA IX was inhibited in the high nanomolar range. 2-Oxo-N-((2-(pyrrolidin-1-yl)ethyl)carbamothioyl)-2H-chromene-3-carboxamide (e11) exhibited a selective inhibitory action against hCA IX with the Ki of 107.9 nM. In order to better understand the inhibitory profiles of studied molecules, multiscale molecular modeling approaches were used. Different molecular docking algorithms were used to investigate binding poses and predicted binding energies of studied compounds at the active sites of the CA I, II, VII and IX isoforms. © 2017 Elsevier B.V., All rights reserved.Publication Open Access Discovery of Klotho peptide antagonists against Wnt3 and Wnt3a target proteins using combination of protein engineering, protein–protein docking, peptide docking and molecular dynamics simulations(Taylor and Francis Ltd [email protected], 2017) 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, TurkeyThe Klotho is known as lifespan enhancing protein involved in antagonizing the effect of Wnt proteins. Wnt proteins are stem cell regulators, and uninterrupted exposure of Wnt proteins to the cell can cause stem and progenitor cell senescence, which may lead to aging. Keeping in mind the importance of Klotho in Wnt signaling, in silico approaches have been applied to study the important interactions between Klotho and Wnt3 and Wnt3a (wingless-type mouse mammary tumor virus (MMTV) integration site family members 3 and 3a). The main aim of the study is to identify important residues of the Klotho that help in designing peptides which can act as Wnt antagonists. For this aim, a protein engineering study is performed for Klotho, Wnt3 and Wnt3a. During the theoretical analysis of homology models, unexpected role of number of disulfide bonds and secondary structure elements has been witnessed in case of Wnt3 and Wnt3a proteins. Different in silico experiments were carried out to observe the effect of correct number of disulfide bonds on 3D protein models. For this aim, total of 10 molecular dynamics (MD) simulations were carried out for each system. Based on the protein–protein docking simulations of selected protein models of Klotho with Wnt3 and Wnt3a, different peptides derived from Klotho have been designed. Wnt3 and Wnt3a proteins have three important domains: Index finger, N-terminal domain and a patch of ∼10 residues on the solvent exposed surface of palm domain. Protein–peptide docking of designed peptides of Klotho against three important domains of palmitoylated Wnt3 and Wnt3a yields encouraging results and leads better understanding of the Wnt protein inhibition by proposed Klotho peptides. Further in vitro studies can be carried out to verify effects of novel designed peptides as Wnt antagonists. © 2017 Elsevier B.V., All rights reserved.Publication Open Access The signaling pathway of dopamine D2 receptor (D2R) activation using normal mode analysis (NMA) and the construction of pharmacophore models for D2R ligands(Taylor and Francis Ltd. [email protected], 2017) Salmas, Ramin Ekhteiari; Stein, Matthias Jeanette; Yurtsever, Mine; Seeman, Philip; Erol, Ismail; Mestanoglu, Mert; Durdagi, Serdar; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir 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, Canada; Erol, Ismail, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Chemistry, Gebze Teknik Üniversitesi, Gebze, Turkey; Mestanoglu, Mert, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyG-protein-coupled receptors (GPCRs) are targets of more than 30% of marketed drugs. Investigation on the GPCRs may shed light on upcoming drug design studies. In the present study, we performed a combination of receptor- and ligand-based analysis targeting the dopamine D2 receptor (D2R). The signaling pathway of D2R activation and the construction of universal pharmacophore models for D2R ligands were also studied. The key amino acids, which contributed to the regular activation of the D2R, were in detail investigated by means of normal mode analysis (NMA). A derived cross-correlation matrix provided us an understanding of the degree of pair residue correlations. Although negative correlations were not observed in the case of the inactive D2R state, a high degree of correlation appeared between the residues in the active state. NMA results showed that the cytoplasmic side of the TM5 plays a significant role in promoting of residue–residue correlations in the active state of D2R. Tracing motions of the amino acids Arg219, Arg220, Val223, Asn224, Lys226, and Ser228 in the position of the TM5 are found to be critical in signal transduction. Complementing the receptor-based modeling, ligand-based modeling was also performed using known D2R ligands. The top-scored pharmacophore models were found as 5-sited (AADPR.671, AADRR.1398, AAPRR.3900, and ADHRR.2864) hypotheses from PHASE modeling from a pool consisting of more than 100 initial candidates. The constructed models using 38 D2R ligands (in the training set) were validated with 15 additional test set compounds. The resulting model correctly predicted the pIC50 values of an additional test set compounds as true unknowns. © 2017 Elsevier B.V., All rights reserved.Publication Open Access A QM protein–ligand investigation of antipsychotic drugs with the dopamine D2 Receptor (D2R)(Taylor and Francis Ltd. [email protected], 2018) Salmas, Ramin Ekhteiari; Serhat Is, Yusuf; Durdagi, Serdar; Stein, Matthias Jeanette; Yurtsever, Mine; Salmas, Ramin Ekhteiari, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Serhat Is, Yusuf, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey, Vocational School Department of Chemistry Technology, Gedik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir 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, TurkeyThe dopamine D2 Receptor (D2R) is a member of the G-Protein-Coupled Receptor family and plays a critical role in neurotransmission activities in the human brain. Dysfunction in dopamine receptor signaling may lead to mental health illnesses such as schizophrenia and Parkinson’s disease. D2R is the target protein of the commonly used antipsychotic drugs such as risperidone, clozapine, aripiprazole, olanzapine, ziprasidone, and quetiapine. Due to their significant side effects and non-selective profiles, the discovery of novel drugs has become a challenge for researchers working in this field. Recently, our group has focused on the interactions of these drug molecules in the active site of the D2R using different in silico approaches. We here compare the performances of different approaches in estimating the drug binding affinities using quantum chemical approaches. Conformations of drug molecules (ligands) at the binding site of the D2R taken from the preliminary docking studies and molecular dynamics simulations were used to generate protein–ligand interaction models. In a first approach, the BSSE-corrected interaction energies of the ligands with the most critical amino acid Asp114 and with the other amino acids closest to ligands in the binding cavity were calculated separately by density functional theory method in implicit water environment at the M06-2X/6-31 g(d,p) level of the theory. In a second approach, ligand binding affinities were calculated by taking into consideration not only the interaction energies but also deformation and desolvation energies of ligands with surrounding amino acid residues, in a radius of 5 Å of the protein-bound ligand. The quantum mechanically obtained results were compared with the experimentally obtained binding affinity values. We concluded that although H-bond interactions of ligands with Asp114 are the most dominant interaction in the binding site, if van der Waals and steric interactions of ligands which have cumulative effect on the ligand binding are not included in the calculations, the interaction energies are overestimated. © 2018 Elsevier B.V., All rights reserved.