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    Computational design of a full-length model of HIV-1 integrase: modeling of new inhibitors and comparison of their calculated binding energies with those previously studied
    (Springer, 2013) Ercan, Selami; Pirinccioglu, Necmettin
    A full-length model of integrase (IN) of the human immunodeficiency virus type 1 (HIV-1) was constructed based on the distinctly resolved X-ray crystal structures of its three domains, named N-terminal, catalytic core and C-terminal. Thirty-one already known inhibitors with varieties of structural differences as well as nine newly tested ones were docked into the catalytic core. The molecular dynamic (MD) and binding properties of these complexes were obtained by MD calculations. The binding energies calculated by molecular mechanic/Poisson Boltzmann solvation area were significantly correlationed with available IC50. Four inhibitors including two newly designed were also docked into the full-length model and their MD behaviors and binding properties were calculated. It was found that one of the newly designed compounds forms a better complex with HIV-1 IN compared to the rest including raltegravir. MD calculations were performed with AMBER suite of programs using ff99SB force field for the proteins and the general Amber force field for the ligands. In conclusion, the results have produced a promising standpoint not only in the construction of the full-length model but also in development of new drugs against it. However, the role of multimer formation and the involvement of DNAs, and their subsequent effect on the complexation and inhibition, are required to arrive at a conclusive decision.
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    Deciphering the complex three-way interaction between the non-integrin laminin receptor, galectin-3 and Neisseria meningitidis
    (Royal Soc, 2014) Alqahtani, Fulwah; Mahdavi, Jafar; Wheldon, Lee M.; Vassey, Matthew; Pirinccioglu, Necmettin; Royer, Pierre-Joseph; Qarani, Suzan M.
    The non-integrin laminin receptor (LAMR1/RPSA) and galectin-3 (Gal-3) are multi-functional host molecules with roles in diverse pathological processes, particularly of infectious or oncogenic origins. Using bimolecular fluorescence complementation and confocal imaging, we demonstrate that the two proteins homo-and heterodimerize, and that each isotype forms a distinct cell surface population. We present evidence that the 37 kDa form of LAMR1 (37LRP) is the precursor of the previously described 67 kDa laminin receptor (67LR), whereas the heterodimer represents an entity that is distinct from this molecule. Site-directed mutagenesis confirmed that the single cysteine (C-173) of Gal-3 or lysine (K-166) of LAMR1 are critical for heterodimerization. Recombinant Gal-3, expressed in normally Gal-3-deficient N2a cells, dimerized with endogenous LAMR1 and led to a significantly increased number of internalized bacteria (Neisseria meningitidis), confirming the role of Gal-3 in bacterial invasion. Contact- dependent cross-linking determined that, in common with LAMR1, Gal-3 binds the meningococcal secretin PilQ, in addition to the major pilin PilE. This study adds significant new mechanistic insights into the bacterial-host cell interaction by clarifying the nature, role and bacterial ligands of LAMR1 and Gal-3 isotypes during colonization.
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    Designing new drug candidates as inhibitors against wild and mutant type neuraminidases: molecular docking, molecular dynamics and binding free energy calculations
    (Taylor & Francis Inc, 2023) Kurt, Murat; Ercan, Selami; Pirinccioglu, Necmettin
    Influenza virus is the cause of the death of millions of people with about 3-4 pandemics every hundred years in history. It also turns into a seasonal disease, bringing about approximately 5-15% of the population to be infected and 290,000-650,000 people to die every year. These numbers reveal that it is necessary to be on the alert to work towards influenza in order to protect public health. There are FDA-approved antiviral drugs such as oseltamivir and zanamivir recommended by the World Center for Disease Prevention. However, after the recent outbreaks such as bird flu and swine flu, increasing studies have shown that the flu virus has gained resistance to these drugs. So, there is an urgent need to find new drugs effective against this virus. This study aims to investigate new drug candidates targeting neuraminidase (NA) for the treatment of influenza by using computer aided drug design approaches. They involve virtual scanning, de novo design, rational design, docking, MD, MMGB/PBSA. The investigation includes H1N1, H5N1, H2N2 and H3N2 neuraminidase proteins and their mutant variants possessing resistance to FDA-approved drugs. Virtual screening consists of approximately 30 thousand molecules while de novo and rational designs produced over a hundred molecules. These approaches produced three lead molecules with binding energies for both non-mutant (-34.84, -59.99 and -60.66 kcal/mol) and mutant (-40.40, -58.93, -76.19 kcal/mol) H2N2 NA calculated by MM-PBSA compared with those of oseltamivir -25.64 and -18.40 respectively. The results offer new drug candidates against influenza infection. Communicated by Ramaswamy H. Sarma
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    Enantiomeric discrimination of chiral organic salts by chiral aza-15-crown-5 ether with C1 symmetry: experimental and theoretical approaches
    (Springer, 2015) Kocakaya, Safak Ozhan; Turgut, Yilmaz; Pirinccioglu, Necmettin
    The work involves an experimental (H-1 NMR) and theoretical (MD, MM-PBSA and DFT) investigation of the molecular recognition and discrimination properties of a chiral aza-15-crown-5 against methyl esters of alanine, phenylalanine and valine hydrochloride salts. The results indicate that the receptor binds enantiomers with moderate binding constants (88-1,389 M-1), with phenylalanine being more discriminated. The difference in experimental binding free energies (Delta G(R) - Delta G(S)) for alanine, phenylalanine and valine enantiomers were calculated as -0.36, -1.58 and 0.80 kcal mol(-1), respectively. The differences in theoretical binding energies were calculated by MM-PBSA (Delta E-PB(R) - Delta E-PB(S)=) as -0.30, -1.45 and 0.88, by B3LYP/6-31+G(d) as -1.17, -0.84 and 0.74 and by M06-2X/6-31+G(d) as -1.40, -3.26 and 1.66 kcal mol(-1). The data obtained give valuable information regarding the molecular recognition mode of the organoammonium complexes of chiral aza-crown ether with C-1 symmetry, which may be relevant to biological systems.
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    Enantiomeric recognition of amino acid ester salts by ?-cyclodextrin derivatives: an experimental and computational study
    (Arkat Usa Inc, 2016) Rezanka, Michal; Stibor, Ivan; Azizoglu, Murat; Turgut, Yilmaz; Pirinccioglu, Necmettin
    beta-cyclodextrin derivatives bearing benzoyl (beta-CD-1) and naphthoyl beta-CD-2) moieties have been synthesized from salicylic acid and 3-hydroxy-2-naphthoic acid by a convenient method in 60% and 58% yields, respectively, and were tested for enantiomeric recognition of amino acid ester derivatives. Their ability to discriminate between various L-/D-amino acid methyl ester hydrochloride salts was examined using the H-1 NMR titration method in DMSO-d(6) at 25 degrees C. beta-CD- 2 produced a fairly good discrimination of tryptophan ester salts with a binding constant of 4041 M-1 for L-salt compared with 2864 M-1 for D-salt, which corresponds to a difference of 0.21 kcal mol(-1) in binding free energies. The binding free energies obtained from molecular dynamic calculation by MM/PB(GB) SA are consistent with those obtained from the experimental results.
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    Experimental and computational evidence for ?-lactone intermediates in the addition of aqueous bromine to disodium dimethyl-maleate and -fumarate
    (Royal Soc Chemistry, 2007) Pirinccioglu, Necmettin; Robinson, James J.; Mahon, Mary F.; Buchanan, J. Grant; Williams, Ian H.
    Structural analysis of the bromo-beta-lactones obtained by addition of bromine to aqueous solutions of disodium 2,3-dimethylmaleate and 2,3-dimethylfumarate reveals stereochemistries opposite to those originally assigned in 1937: cis alkene yields erythro lactone, and trans alkene yields threo lactone. B3LYP/6-31+G(d) calculations using a PCM description of aqueous solvation confirm the validity of our proposed mechanism, in which the first-formed intermediate in each case is an a-lactone. The cyclic bromonium species is not an intermediate. An alternative pathway leading directly from cis alkene to cis lactone, via an unusual frontside displacement mechanism, is over 20 kJ mol(-1) higher in free energy. Hydrolysis of the bromo-beta-lactones yields bromohydrins whose stereochemistries as determined by X-ray crystallography indicate stereospecific formation by acyl-oxygen cleavage of the lactone ring, again contrary to the original view.
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    Experimental and theoretical study of the mechanism of hydrolysis of substituted phenyl hexanoates catalysed by globin in the presence of surfactant
    (Springer, 2014) Ercan, Selami; Arslan, Nevin; Kocakaya, Safak Ozhan; Pirinccioglu, Necmettin; Williams, Andrew
    The bimolecular rate constants for the globin-and alkali-catalysed hydrolysis of substituted phenyl hexanoates in the absence and presence of cetyltrimethylammonium bromide (CTAB) obey Bronsted equations with beta(1g)=-0.53 (globin-catalysed), -0.68 (globin-catalysed in CTAB), -0.34 (in water) and -0.74 (in CTAB), respectively. The slopes indicate that the microsolvation environments associated with the transition states of the catalysed reactions are different from those that occur in aqueous medium. The slope (-0.74) for the reaction in CTAB implies that it proceeds in a less polar medium. The larger beta(1g) value (-0.53) obtained for the globin-catalysed reaction compared to that for the uncatalysed one may be attributed to either the less polar microenvironments of the transition states or the involvement of one of the imidazole groups as a nucleophile. The results from a study of the effect of pH on the reactivity provide evidence for the latter assumption. All of the ligands were docked into the hydrophobic pocket of the protein, and the resulting docking scores ranged from -30.76 to -23.61 kcal mol(-1). Molecular dynamic simulations and MM-PBSA/GBSA calculations performed for the complexes gave insight into the binding modes of globin to the esters, which are consistent with experimental results. The calculations yielded comparable free energies of binding to the experimental ones for 4-nitrophenyl and 4-chloro-2-nitrophenyl hexanoates. In conclusion, information obtained from the linear free-energy relationship is still very useful for elucidating the mechanisms of organic reactions, including enzyme-catalysed reactions. This approach is further supported by the utilization of computational tools.
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    A facile synthesis of amide-based receptors under microwave conditions: investigation of their anion recognition properties by experimental and computational tools
    (Springer, 2017) Ozturk, Gulsen; Subari, Salih; Seker, Sevil; Togrul, Mahmut; Kocakay, Safak Ozhan; Ercan, Selami; Pirinccioglu, Necmettin
    Two novel amide-based receptors were synthesized under microwave irradiation. Their chemical structures were confirmed by IR, H-1 NMR, C-13 NMR, and elemental analysis. The binding properties of these amide-based receptors to various anions (H2PO4-, HSO4-, C6H5CO2-, CH3CO2-, ClO4-, F-, Cl-, and Br-) were examined by UV titration in THF at 20 degrees C. The results indicated that the receptors form 1: 1 complexes with anions and they have the strongest affinity for fluoride (F-) among the anions considered. Molecular dynamics calculations by AMBER and quantum mechanical calculations performed at the B3LYP and M062X levels of theory using the 6-31 + g(d,p) basis set provided models for the complexation mode between the receptors and anions and yielded binding energies for the complexes.
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    The isolation of tetrangomycin from terrestrial Streptomyces sp CAH29: evaluation of antioxidant, anticancer, and anti-MRSA activity
    (Springer Birkhauser, 2016) Ozakin, Suleyman; Davis, Robert W.; Umile, Thomas P.; Pirinccioglu, Necmettin; Kizil, Murat; Celik, Gurbet; Sen, Alaattin
    A rhizosphere isolate Streptomyces sp. CAH29 was found to possess potent antibacterial and antifungal activity against a variety of test organisms. Based on 16S ribosomal ribonucleic acid sequence homology studies, this strain was found to be similar to Streptomyces stramineus (gene sequence similarity 99 %). The major bioactive metabolite produced by Streptomyces sp. CAH29 isolate was extracted, purified andidentified by nuclear magnetic resonance as tetrangomycin. This known anthraquinone-exhibited antimicrobial activity against Staphylococcus aureus, Streptococcus pyogenes, methicillin resistant Staphylococcus aureus and Candida albicans with inhibition zones of 14, 10, 12 and 8 mm, respectively. Docking results demonstrate that tetrangomycin has a similar mode of action and a comparable docking score to bind to the dehydrosqualene synthase (CrtM) enzyme of methicillin resistant Staphylococcus aureus compared to the current inhibitor. Hence, this suggests that tetrangomycin has a potential to be used as an anti-methicillin resistant Staphylococcus aureus agent. Tetrangomycin also showed moderate free radical scavenging activity with 1,1-diphenyl-2-picryl-hydrazil. Tetrangomycin apparently decreased all of the studied cytokine (pro-inflammatory: interleukin 1B, interleukin 2, tumor necrosis factor and interleukin L6 and anti-inflammatory: interleukin 10) expression levels at IC50 concentrations in A459 (adenocarcinomic human alveolar basal epithelial) and LNCAP (human prostate adenocarcinoma) cell lines. In addition, it reduced Caspase 8 and 3 mRNA levels in LNCAP and A549 cells. This study describes for the first time novel in vitro immunosuppressive function of tetrangomycin by reducing the transcription of cytokine genes.
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    Novel bis(aminoalcohol)oxalamide organogelators and their diglycolylamide analogs: evaluation of gelation efficiency in various organic fluids
    (Tubitak Scientific & Technological Research Council Turkey, 2017) Colak, Mehmet; Baris, Deniz; Pirinccioglu, Necmettin; Hosgoren, Halil
    Three modular types of bis(aminoalcohol)oxalamides (1, 4, and 7) and bis(aminoalcohol)diglycolylamide (8) gelators have been prepared by the reaction of the respective aminoalcohols with oxalyl and digycolyl methylesters as potential low-molecular-weight organogelators. The gelation properties of these amides have been evaluated in various aromatic organic solvents (xylene, toluene, isopropyl benzene, and aromatic ether type organic fluids such as anisole or alpha-phenylethylmethylether) as well as the long-chain aliphatic alcohols (1-hexanol, 1-octanol, 2-octanol, and aromatic 1-phenylethanol). The compounds with sec-butyl and ethyl side chains produce good gelation properties in both aromatic and other organic fluids. Furthermore, the common oxalamide linker present in the gelators was replaced by an extended diglycolylamide linker (8) and its behaviors were compared with the benzylic oxalamide analog (3). The gelator (8) gives the best results with aromatic fluid and lauric acid ethyl ester. H-1 NMR studies reveal the existence of temperature dependent network assembly/dissolution equilibrium and produce K-gel. FTIR was employed to see the effect of hydrogen bonding in the formation of gel network. Thermodynamic parameters regarding gel-to-sol transition were collected with van't Hoff relationships.
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    A novel O-linked glycan modulates Campylobacter jejuni major outer membrane protein-mediated adhesion to human histo-blood group antigens and chicken colonization
    (Royal Soc, 2014) Mahdavi, Jafar; Pirinccioglu, Necmettin; Oldfield, Neil J.; Carlsohn, Elisabet; Stoof, Jeroen; Aslam, Akhmed; Self, Tim
    Campylobacter jejuni is an important cause of human foodborne gastroenteritis; strategies to prevent infection are hampered by a poor understanding of the complex interactions between host and pathogen. Previous work showed that C. jejuni could bind human histo-blood group antigens (BgAgs) in vitro and that BgAgs could inhibit the binding of C. jejuni to human intestinal mucosa ex vivo. Here, the major flagella subunit protein (FlaA) and the major outer membrane protein (MOMP) were identified as BgAg-binding adhesins in C. jejuni NCTC11168. Significantly, the MOMP was shown to be O-glycosylated at Thr(268); previously only flagellin proteins were known to be O-glycosylated in C. jejuni. Substitution of MOMP Thr(268) led to significantly reduced binding to BgAgs. The O-glycan moiety was characterized as Gal(beta 1-3)-GalNAc(beta 1-4)-GalNAc(beta 1-4)-GalNAca1-Thr(268); modelling suggested that O-glycosylation has a notable effect on the conformation of MOMP and this modulates BgAg-binding capacity. Glycosylation of MOMP at Thr(268) promoted cell-to-cell binding, biofilm formation and adhesion to Caco-2 cells, and was required for the optimal colonization of chickens by C. jejuni, confirming the significance of this O-glycosylation in pathogenesis.
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    A series of novel ?-hydroxyamide based catalysts for borane-mediated enantioselective reductions of prochiral ketones
    (Pergamon-Elsevier Science Ltd, 2016) Azizoglu, Murat; Erdogan, Asli; Arslan, Nevin; Turgut, Yilmaz; Hosgoren, Halil; Pirinccioglu, Necmettin
    The enantioselective reduction of prochiral ketones with borane in the presence of a chiral ligand has received considerable attention. Hydroxylamine-based chiral ligands with amide and hydroxyl functions in the presence of other co-ordinating groups are highly effective in these asymmetric reductions. The current work presents a simple one step synthesis of a series of beta-hydroxyamide-based ligands from the reaction between 3-hydroxy-2-naphthoic acid and chiral amino alcohols and their applications as catalysts in asymmetric borane-mediated reductions of aromatic prochiral ketones in THE The reductions provided the corresponding secondary alcohols with up to 96% ee and in good to excellent yields (89-99%). OFF calculations at B3LYP/6-31+g(d) level offered theoretical models to account for the enantioselectivity imposed by the chiral ligands in the reductions of the ketones. (C) 2016 Elsevier Ltd. All rights reserved.
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    Synthesis of new diaza-18-crown-6 ethers derived from trans-(R,R)-1,2-diaminocyclohexane and investigation of their enantiomeric discrimination ability with amino acid ester salts
    (Pergamon-Elsevier Science Ltd, 2013) Karakaplan, Mehmet; Ak, Devran; Colak, Mehmet; Kocakaya, Safak Ozhan; Hosgoren, Halil; Pirinccioglu, Necmettin
    The synthesis of four diaza-18-crown-6 ethers with C-2-symmetry derived from trans-(R,R)-1,2-diaminocyclohexane bearing methyl, phenyl and phenoxymethyl moeities attached to a stereogenic centre on the crown ring were achieved. Enantiomeric discrimination of these macrocycles against amino acid methyl ester salts was examined by H-1 NMR titration method. They exhibit strong binding ability and some of them show a very high enantioselectivity towards amino acid esters, corresponding to 537 kJ/mol of binding energy difference in CDCl3 at 25 degrees C. Computational modelling showed parallel results with experimental calculations, thus providing a detailed understanding of molecular recognition mode and binding sites between the hosts and the guests. (C) 2012 Elsevier Ltd. All rights reserved.
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    Synthesis of rigid and C2-symmetric pyridino-15-crown-5 type macrocycles bearing diamide-diester functions: enantiomeric recognition for chiral primary organoammonium perchlorate salts
    (Pergamon-Elsevier Science Ltd, 2014) Seker, Sevil; Baris, Deniz; Arslan, Nevin; Turgut, Yilmaz; Pirinccioglu, Necmettin; Togrul, Mahmut
    Four novel C-2-symmetric macrocyclic compounds with a pyridine function and possessing amide and ester lingeages were prepared. The enantiomeric discrimination abilities of these macrocycles against alpha-phenylethylammonium and alpha-(1-naphthyl)ethylammonium perchlorate salts were measured by standard H-1 NMR titration techniques in DMSO-d(6). A binding constant ratio of 31 (Kbind(S)/Kbind(R)) for two enantiomers of alpha-(1-naphthyl)ethylammonium salt with the macrocyclic host (S,S)-4 bearing phenyl arms was observed, which corresponds to an enantiomeric discrimination of approximately 94%. Molecular dynamic calculations were performed for some of the supramolecular complexes to in order to gain insight into the mode of molecular recognition between the macrocyclic compounds and ammonium salts; these results were consistent with experimental observations, which may be relevant to those in biochemical processes occurring in organisms. (C) 2014 Elsevier Ltd. All rights reserved.
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    A theoretical study of the effects of polar substitution on the activation barriers for internal rotation around the C-N bond in p-substituted nitrosobenzenes: comparison of DFT and MP2 calculations
    (Tubitak Scientific & Technological Research Council Turkey, 2010) Kocakaya, Safak Oezhan; Pirinccioglu, Necmettin
    The activation barriers for internal rotation around the C-N bond in p-substituted nitrosobenzenes were calculated using the density functional theory (DFT) and second-order Moller-Plesset (MP2) methods with the 6-31+g(d) basis set. The polarisable continuum model (PCM) was used to model the solvent effect. An explicit water molecule was also introduced to form a hydrogen bond with the nitroso group and its effect on the barrier was studied by DFT. The barriers were well-correlated with Hammett sigma(+) rather than sigma values, meaning a strong resonance effect on the transition state. The MP2 method produces better and comparable results with the few available experimental values.