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Publication Metadata only Discovery of selective dengue virus inhibitors using combination of molecular fingerprint-based virtual screening protocols, structure-based pharmacophore model development, molecular dynamics simulations and in vitro studies(ELSEVIER SCIENCE INC, 2018) Mirza, Shaher Bano; Lee, Regina Ching Hua; Chu, Justin Jang Hann; Salmas, Ramin Ekhteiari; Mavromoustakos, Thomas; Durdagi, Serdar; Bahcesehir University; Massachusetts Institute of Technology (MIT); COMSATS University Islamabad (CUI); National University of Singapore; National & Kapodistrian University of AthensDengue virus is a major issue of tropical and sub-tropical regions. The proliferation of virus results in immense number of deaths each year because of unavailability of on-shelf drugs. This issue necessitates the design of novel anti-Dengue drugs. 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. Keeping in mind the worsening situation regarding Dengue virus, approximately eighteen million drug-like compounds from the ZINC small molecule database have been screened against Nonstructural Protein 3 (NS3) previously by our group. In this study, in order to investigate the effect of extended time of molecular dynamics (MD) simulations on structural and dynamical profiles of used complexes, simulation run time is increased from 50-ns to 100-ns for the each system. In addition, a well-known Dengue virus inhibitor (MB21) from literature is used as reference structure (positive control) to compare the proposed molecules. Post-processing MD analyses including Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations were conducted to predict binding free energies of inhibitors from derived trajectory frames of MD simulations. Identified compounds are further directed to Quantum-Polarized Ligand Docking (QPLD), molecular fingerprint-based virtual screening of another small molecule database (Otava Drug Like small molecule database), and Structure-based Pharmacophore Modeling (E-Pharmacophore). Finally, cell proliferation and cytotoxicity tests as well as pre and post-treatment on HUH7 cells infected with DENV2 NGC strain are applied for four identified hit molecules (ZINC36681949, ZINC44921800, ZINC95518765 and ZINC39500661) to check whether these drugs inhibit DENV2 from entry and/or exit pathways. Based on cell-based Dengue quantification assays, there is no effect seen on pre-treatment of cells with these compounds indicating that the early infection processes of virus is not affected. In contrast, the post-treatment of cells with these compounds after Dengue virus infection has resulted in a significant 1 log PFU/ml reduction of the virus infectious titre. (C) 2017 Elsevier Inc. All rights reserved.Publication Metadata only Carbonic anhydrase inhibitors: Design, synthesis, kinetic, docking and molecular dynamics analysis of novel glycine and phenylalanine sulfonamide derivatives(PERGAMON-ELSEVIER SCIENCE LTD, 2015) Fidan, Ismail; Salmas, Ramin Ekhteiari; Arslan, Mehmet; Senturk, Murat; Durdagi, Serdar; Ekinci, Deniz; Senturk, Esra; Cosgun, Sedat; Supuran, Claudiu T.; Gebze Technical University; Yalova University; Agri Ibrahim Cecen University; Bahcesehir University; Ondokuz Mayis University; Agri Ibrahim Cecen University; Fatih University; University of FlorenceThe 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 K-I values in the range of 14.66-315 mu M for hCA I and of 18.31-143.8 mu M 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-nitro-phenylacetate 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. (C) 2015 Elsevier Ltd. 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 PUBL LTD, 2016) Kellici, Tahsin F.; Ntountaniotis, Dimitrios; Kritsi, Eftichia; Zervou, Maria; Zoumpoulakis, Panagiotis; Potamitis, Constantinos; Durdagi, Serdar; Salmas, Ramin Ekhteiari; Ergun, Gizem; Gokdemir, Ebru; Halabalaki, Maria; Gerothanassis, Ioannis P.; Liapakis, George; Tzakos, Andreas G.; Mavromoustakos, Thomas; University of Ioannina; National & Kapodistrian University of Athens; National Hellenic Research Foundation; Bahcesehir University; Bahcesehir University; National & Kapodistrian University of Athens; University of CreteThe 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.Publication Metadata only Carbonic anhydrase inhibitory properties of novel benzylsulfamides using molecular modeling and experimental studies(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2014) Goksu, Suleyman; Naderi, Ali; Akbaba, Yusuf; Kalin, Pinar; Akincioglu, Akin; Gulcin, Ilhami; Durdagi, Serdar; Salmas, Ramin Ekhteiari; Ataturk University; Erzurum Technical University; Agri Ibrahim Cecen University; King Saud University; Bahcesehir University; Istanbul Technical UniversityIn 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. K-i 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. (C) 2014 Elsevier Inc. All rights reserved.Publication Metadata only Acetylcholinesterase and carbonic anhydrase inhibitory properties of novel urea and sulfamide derivatives incorporating dopaminergic 2-aminotetralin scaffolds(PERGAMON-ELSEVIER SCIENCE LTD, 2016) Ozgeris, Bunyamin; Goksu, Suleyman; Kose, Leyla Polat; Gulcin, Ilhami; Salmas, Ramin Ekhteiari; Durdagi, Serdar; Tumer, Ferhan; Supuran, Claudiu T.; Erzurum Technical University; Ataturk University; King Saud University; Bahcesehir University; Kahramanmaras Sutcu Imam University; University of Florence; University of FlorenceIn the present study a series of urea and sulfamide compounds incorporating the tetralin scaffolds were synthesized and evaluated for their acetylcholinesterase (AChE), human carbonic anhydrase (CA, EC 4.2.1.1) isoenzyme I, and II (hCA I and hCA II) inhibitory properties. The urea and their sulfamide analogs were synthesized from the reactions of 2-aminotetralins with N,N-dimethylcarbamoyl chloride and N,N-dimethylsulfamoyl chloride, followed by conversion to the corresponding phenols via O-demethylation with BBr3. The novel urea and sulfamide derivatives were tested for inhibition of hCA I, II and AChE enzymes. These derivatives exhibited excellent inhibitory effects, in the low nanomolar range, with K-i values of 2.61-3.69 nM against hCA I, 1.64-2.80 nM against hCA II, and in the range of 0.45-1.74 nM against AChE. In silico techniques such as, atomistic molecular dynamics (MD) and molecular docking simulations, were used to understand the scenario of the inhibition mechanism upon approaching of the ligands into the active site of the target enzymes. In light of the experimental and computational results, crucial amino acids playing a role in the stabilization of the enzyme-inhibitor adducts were identified. (C) 2016 Elsevier Ltd. All rights reserved.Publication Metadata only The signaling pathway of dopamine D2 receptor (D2R) activation using normal mode analysis (NMA) and the construction of pharmacophore models for D2R ligands(TAYLOR & FRANCIS INC, 2017) Salmas, Ramin Ekhteiari; Stein, Matthias; Yurtsever, Mine; Seeman, Philip; Erol, Ismail; Mestanoglu, Mert; Durdagi, Serdar; Bahcesehir University; Max Planck Society; Istanbul Technical University; University of Toronto; Gebze Technical UniversityG-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 pIC(50) values of an additional test set compounds as true unknowns.Publication Metadata only The effects of pollen, propolis, and caffeic acid phenethyl ester on tyrosine hydroxylase activity and total RNA levels in hypertensive rats caused by nitric oxide synthase inhibition: experimental, docking and molecular dynamic studies(TAYLOR & FRANCIS INC, 2018) Salmas, Ramin Ekhteiari; Durdagi, Serdar; Gulhan, Mehmet Fuat; Duruyurek, Merve; Abdullah, Huda I.; Selamoglu, Zeliha; Bahcesehir University; Nigde Omer Halisdemir University; New York Medical CollegeThe objective of the present study was to evaluate the effects of propolis, pollen, and caffeic acid phenethyl ester (CAPE) on tyrosine hydroxylase (TH) activity and total RNA levels of N-nitro-L-arginine methyl ester (L-NAME) inhibition of nitric oxide synthase in the heart, adrenal medulla, and hypothalamus of hypertensive male Sprague dawley rats. The TH activity in the adrenal medulla, heart, and hypothalamus of the rats was significantly increased in the L-NAME group vs. control (p<0.05). Treatment with L-NAME led to a significant increase in blood pressure (BP) in the L-NAME group compared to control (p<0.05). These data suggest that propolis, pollen, and CAPE may mediate diminished TH activity in the heart, adrenal medulla, and hypothalamus in hypertensive rats. The decreased TH activity may be due to the modulation and synthesis of catecholamines and BP effects. In addition, the binding mechanism of CAPE within the catalytic domain of TH was investigated by means of molecular modeling approaches. These data suggest that the amino acid residues, Glu429 and Ser354 of TH may play a pivotal role in the stabilization of CAPE within the active site as evaluated by molecular dynamics (MD) simulations. Gibbs binding free energy (G(binding)) of CAPE in complex with TH was also determined by post-processing MD analysis approaches (i.e. Poisson-Boltzmann Surface Area (MM-PBSA) method).Publication Metadata only Analysis of the Glutamate Agonist LY404,039 Binding to Nonstatic Dopamine Receptor D2 Dimer Structures and Consensus Docking(AMER CHEMICAL SOC, 2017) Salmas, Ramin Ekhteiari; Seeman, Philip; Aksoydan, Busecan; Erol, Ismail; Kantarcioglu, Isik; Stein, Matthias; Yurtsever, Mine; Durdagi, Serdar; Bahcesehir University; University of Toronto; University of Toronto; Gebze Technical University; Max Planck Society; Istanbul Technical UniversityDopamine receptor D2 (D2R) plays an important role in the human central nervous system and is a focal target of antipsychotic agents. The D2(High)R and D2(Low)R dimeric models previously developed by our group are used to investigate the prediction of binding affinity of the LY404,039 ligand and its binding mechanism within the catalytic domain. The computational data obtained using molecular dynamics simulations fit well with the experimental results. The calculated binding affinities of LY404,039 using MM/PBSA for the D2(High)R and D2(Low)R targets were -12.04 and -9.11 kcal/mol, respectively. The experimental results suggest that LY404,039 binds to D2(High)R and D2L(ow)R with binding affinities (K-i) of 8.2 and 1640 nM, respectively. The high binding affinity of LY404,039 in terms of binding to [H-3]domperidone was inhibited by the presence of a guanine nucleotide, indicating an agonist action of the drug at D2(High)R. The interaction analysis demonstrated that while Asp114 was among the most critical amino acids for D2(High)R binding, residues Ser193 and Ser197 were significantly more important within the binding cavity of D2(Low)R Molecular modeling analyses are extended to ensemble docking as well as structure-based pharmacophore model (E-pharmacophore) development using the bioactive conformation of LY404,039 at the binding pocket as a template and screening of small-molecule databases with derived pharmacophore models.Publication Metadata only Combinatorial peptide library screening for discovery of diverse α-glucosidase inhibitors using molecular dynamics simulations and binary QSAR models(TAYLOR & FRANCIS INC, 2019) Mollica, Adriano; Zengin, Gokhan; Durdagi, Serdar; Salmas, Ramin Ekhteiari; Macedonio, Giorgia; Stefanucci, Azzurra; Dimmito, Marilisa Pia; Novellino, Ettore; G d'Annunzio University of Chieti-Pescara; Selcuk University; Bahcesehir University; Bahcesehir University; University of Naples Federico IIHuman alpha-glucosidase is an enzyme involved in the catalytic cleavage of the glucoside bond and involved in numerous functionalities of the organism, as well as in the insurgence of diabetes mellitus 2 and obesity. Thus, developing chemicals that inhibit this enzyme is a promising approach for the treatment of several pathologies. Small peptides such as di- and tri-peptides may be in natural organism as well as in the GI tract in high concentration, coming from the digestive process of meat, wheat and milk proteins. In this work, we reported the first tentative hierarchical structure-based virtual screening of peptides for human alpha-glucosidase. The goal of this work is to discover novel and diverse lead compounds that my act as inhibitors of alpha-glucosidase such as small peptides by performing a computer aided virtual screening and to find novel scaffolds for further development. Thus, in order to select novel candidates with original structure we performed molecular dynamics (MD) simulations among the 12 top-ranked peptides taking as comparison the MD simulations performed on crystallographic inhibitor acarbose. The compounds with the lower RMSD variability during the MD, were reserved for in vitro biological assay. The selected 4 promising structures were prepared on solid phase peptide synthesis and used for the inhibitory assay, among them compound 2 showed good inhibitory activity, which validated our method as an original strategy to discover novel peptide inhibitors. Moreover, pharmacokinetic profile predictions of these 4 peptides were also carried out with binary QSAR models using MetaCore/MetaDrug applications.Publication Metadata only In vitro and in silico approaches to appraise Polygonum maritimum. L. as a source of innovative products with anti-ageing potential(ELSEVIER SCIENCE BV, 2018) Rodrigues, Maria Joao; Slusarczyk, Sylwester; Pecio, Lukasz; Matkowski, Adam; Salmas, Ramin Ekhteiari; Durdagi, Serdar; Pereira, Catarina; Varela, Joao; Barreira, Luisa; Custodio, Luisa; Universidade do Algarve; Wroclaw Medical University; Bahcesehir University; Institute of Soil Science & Plant CultivationDifferent Polygonum species have in vitro neuroprotective properties and are traditionally used for their anti ageing benefits. In this context this work explored for the first time P. maritimum (sea knotgrass) as a potential source of natural products with industrial application as cognitive enhancers with anti-ageing potential. For that purpose methanol and dichloromethane extracts were prepared from leaves and roots of that species and evaluated for in vitro neuroprotective effects through the inhibition on acetyl- (AChE) and butyrylcholinesterase (BuChE), protection against hydrogen peroxide (H2O2)-induced cytoxicity on neuroblastoma cells and lipopolysaccharide (LPS)-induced neuroinflammation on microglia cells. The extracts were chemically characterized by ultra-high-pressure liquid chromatography (UHPLC) coupled to tandem mass spectrometry (MS/MS) and docking studies were performed on the identified compounds. Methanol extracts had the highest activity in AChE (leaves: IC50 = 0.27 mg/mL, roots: IC50 = 0.17 mg/mL) and BuChE (leaves: IC50 = 0.62 mg/mL, roots: IC50 = 0.61 mg/mL) inhibition, as well as reduction of nitric oxide (NO) production in LPS-treated microglia (leaves: IC50 = 4.17 mu g/mL, roots: ICso = 9.95 mu g/mL). Methanol extracts prevented oxidative stress-induced cytotoxicity in SH-SY5Y cells when applied simultaneously with H2O2, whereas cells pre-treated with the dichloromethane extracts had increased viability. Fifteen flavonoids were identified and showed favorable binding energies to AChE and BuChE binding pockets. These data suggests P. maritimum as a promising source of natural products and/or molecules with cognitive enhancement and anti-ageing properties.