Araştırma Çıktıları | WoS | Scopus | TR-Dizin | PubMed
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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 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 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.