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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 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 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 Discovering novel carbonic anhydrase type IX (CA IX) inhibitors from seven million compounds using virtual screening and in vitro analysis(Taylor and Francis Ltd [email protected], 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.Publication Metadata only Atomistic molecular dynamics simulations of typical and atypical antipsychotic drugs at the dopamine D2 receptor (D2R) elucidates their inhibition mechanism(Taylor and Francis Ltd. [email protected], 2017) Salmas, Ramin Ekhteiari; Yurtsever, Mine; Durdagi, Serdar; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyDopamine D2 receptor (D2R) plays a pivotal role in nervous systems. Its dysfunction leads to the schizophrenia, Parkinson’s diseases and drug addiction. Since the crystal structure of the D2R was not solved yet, discovering of potent and highly selective anti-psychotic drugs carry challenges for different neurodegenerative diseases. In the current study, we modeled the three-dimensional (3D) structure of the D2R based on a recently crystallized structure of the dopamine D3 receptor. These two receptors share a high amino acid sequence homology (>70%). The interaction of the modeled receptor with well-known atypical and typical anti-psychotic drugs and the inhibition mechanisms of drugs at the catalytic domain were studied via atomistic molecular dynamics simulations. Our results revealed that, class-I and class-II forms of atypical and typical D2R antagonists follow different pathways in the inhibition of the D2Rs. © 2017 Elsevier B.V., All rights reserved.Publication Metadata only Biological Insights of the Dopaminergic Stabilizer ACR16 at the Binding Pocket of Dopamine D2 Receptor(American Chemical Society [email protected], 2017) Salmas, Ramin Ekhteiari; Seeman, Philip; Aksoydan, Busecan; Stein, Matthias Jeanette; Yurtsever, Mine; Durdagi, Serdar; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Seeman, Philip, Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Canada; Aksoydan, Busecan, 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; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyThe dopamine D2 receptor (D2R) plays an important part in the human central nervous system and it is considered to be a focal target of antipsychotic agents. It is structurally modeled in active and inactive states, in which homodimerization reaction of the D2R monomers is also applied. The ASP2314 (also known as ACR16) ligand, a D2R stabilizer, is used in tests to evaluate how dimerization and conformational changes may alter the ligand binding space and to provide information on alterations in inhibitory mechanisms upon activation. The administration of the D2R agonist ligand ACR16 [3H](+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ((+)PHNO) revealed Ki values of 32 nM for the D2highR and 52 μM for the D2lowR. The calculated binding affinities of ACR16 with post processing molecular dynamics (MD) simulations analyses using MM/PBSA for the monomeric and homodimeric forms of the D2highR were -9.46 and -8.39 kcal/mol, respectively. The data suggests that the dimerization of the D2R leads negative cooperativity for ACR16 binding. The dimerization reaction of the D2highR is energetically favorable by -22.95 kcal/mol. The dimerization reaction structurally and thermodynamically stabilizes the D2highR conformation, which may be due to the intermolecular forces formed between the TM4 of each monomer, and the result strongly demonstrates dimerization essential for activation of the D2R. © 2017 Elsevier B.V., All rights reserved.Publication Metadata only Virtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of in silico and in vitro studies(Taylor and Francis Ltd. [email protected], 2017) Salmas, Ramin Ekhteiari; Ünlü, Ayhan; Bektaş, Muhammet; Yurtsever, Mine; Mestanoglu, Mert; Durdagi, Serdar; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Ünlü, Ayhan, Department of Biophysics, Trakya Üniversitesi, Edirne, Turkey; Bektaş, Muhammet, Department of Biophysics, İstanbul Tıp Fakültesi, Istanbul, Turkey; Yurtsever, Mine, 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, TurkeyPoly(ADP-ribose) polymerase-1 (PARP-1) enzyme has critical roles in DNA replication repair and recombination. Thus, PARP-1 inhibitors play an important role in the cancer therapy. In the current study, we have performed combination of in silico and in vitro studies in order to discover novel inhibitors against PARP-1 target. Structure-based virtual screening was carried out for an available small molecules database. A total of 257,951 ligands from Otava database were screened at the binding pocket of PARP-1 using high-throughput virtual screening techniques. Filtered structures based on predicted binding energy results were then used in more sophisticated molecular docking simulations (i.e. Glide/standard precision, Glide/XP, induced fit docking–IFD, and quantum mechanics polarized ligand docking–QPLD). Potential high binding affinity compounds that are predicted by molecular simulations were then tested by in vitro methods. Computationally proposed compounds as PARP-1 inhibitors (Otava Compound Codes: 7111620047 and 7119980926) were confirmed by in vitro studies. In vitro results showed that compounds 7111620047 and 7119980926 have IC50 values of 0.56 and 63 μM against PARP-1 target, respectively. The molecular mechanism analysis, free energy perturbation calculations using long multiple molecular dynamics simulations for the discovered compounds which showed high binding affinity against PARP-1 enzyme, as well as structure-based pharmacophore development (E-pharmacophore) studies were also studied. © 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.