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Öğe 4D-QSAR Study of p56lck Protein Tyrosine Kinase Inhibitory Activity of Flavonoid Derivatives Using MCET Method(Korean Chemical Soc, 2011) Yilmaz, Hayriye; Guzel, Yahya; Onal, Zulbiye; Altiparmak, Gokce; Kocakaya, Safak OzhanA four dimensional quantitative structure activity relationship analysis was applied to a series of 50 flavonoid inhibitors of p56(lck) protein tyrosine kinase by the molecular comparative electron topological method. It was found that the -log (IC50) values of the compounds were highly dependent on the topology, size and electrostatic character of the substituents at seven positions of the flavonoid scaffold in this study. Depending on the negative or positive charge of the groups correctly embedded in these substituents, three-dimensional bio-structure to increase or decrease -log (IC50) values in the training set of 39 compounds was predicted. The test set of 11 compounds was used to evaluate the predictivity of the model. To generate 4D-QSAR model, the defined function groups and pharmacophore used as topological descriptors in the calculation of activity were of sufficient statistical quality (R-2 = 0.72 and Q(2) = 0.69). Ligand docking approach by using Dock 6.0. These compounds include many flavonoid analogs, They were docked onto human families of p56lck PTKs retrieved from the Protein Data Bank, 11kl.pdb.Öğe Complexation and transport of amino acid esters and their salts with synthesised chiral novel aza crown ether derivatives(Taylor & Francis Ltd, 2014) Kazaylek, Mehmet; Kocakaya, Safak Ozhan; Oral, Elif Varhan; Colak, Mehmet; Karakaplan, MehmetThe syntheses of four aza-15-crown-5 ethers bearing phenyl and phenoxymethyl moieties attached to a stereogenic centre on the crown ring were achieved. Macrocycles have exhibited strong binding ability (K-a=5364-12,969M(-1)) and modest enantiomeric discrimination towards the enantiomers of amino acid methyl ester salts by UV titration method in CHCl3 at 25 degrees C. Computer modelling results supported experimental data providing a detailed understanding of the molecular recognition mode between hosts and guests and the likely binding sites involved. Macrocycles were used for chiral discrimination of amino acids in their zwitterionic forms or as potassium and sodium salts in transport experiments across a bulk chloroform membrane with satisfactory selectivity.Öğe 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, NecmettinThe 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.Öğe The enantiomeric recognition of chiral organic ammonium salts by chiral pyridino-macrocycles bearing aminoalcohol subunits(Pergamon-Elsevier Science Ltd, 2009) Ozer, Hayriye; Kocakaya, Safak Ozhan; Akgun, Abuzer; Hosgoren, Halil; Togrul, MahmutPyridine-based macrocycles were prepared by treating 2,6-bis[[2'6'-bis(bromomethyl)-4'-methylphenoxy]methyl]pyridine 3 with the appropriate chiral aminoalcohols. The enantiomeric recognition of these macrocycles bearing aminoalcohol subunits of the pyridinocrown type ligand was evaluated for chiral organic ammonium salts by UV titration. The important differences were observed in the K-a values of (R)-Am2 and (S)-Am2 for (S,S,S)-1, (S,SS)-2 and (S,S,S)-3 hosts, K-S/K-R = 5.0, K-S/K-R = 2.4 and K-S/K-R = 5.0. respectively. There seems to be a general tendency for hosts to recognise (S)-enantiomers for both Am1 and Am2. (C) 2009 Elsevier Ltd. All rights reserved.Öğe Enantioselective complexation of chiral lariat crown ethers and chiral primary alkylammonium perchlorates(Tubitak Scientific & Technological Research Council Turkey, 2011) Koylu, M. Zafer; Aral, Tarik; Karakaplan, Mehmet; Kocakaya, Safak Ozhan; Hosgoren, HalilIn order to investigate the enantiomeric recognition abilities toward 2 chiral alkylammonium perchlorates (AmI, AmII) by H-1-NMR titration method in CDCl3, 4 chiral lariat ethers 8-11 with a (p-methoxyphenoxy) methyl flexible side arm were used. The most effective enantiomeric recognition was obtained by LCEs 9 and 11 toward AmII, by K-R/K-S 6.58 and K-S/K-R 6.63, respectively. The effect of macroring size, subunit of macroring, and side arm appeared to have strong influence on the binding ability of these alkylammonium ions.Öğe Essential oil content, in-vitro and in-silico activities of Hypericum triquetrifolium Turra, H. empetrifolium subsp. empetrifolium Willd., and H. pruinatum Boiss. & Balansa species(Istanbul Univ, Fac Pharmacy, 2023) Akdeniz, Mehmet; Yener, Ismail; Kocakaya, Safak Ozhan; Yolcu, Murat; Yigitkan, Serkan; Aydin, Firat; Turkmenoglu, Fatma PinarBackground and Aims: The importance of Hypericum species that are used traditionally against many diseases is increasing day by day.Methods: In this study, the essential oil contents of Hypericum triquetrifolium, H. empetrifolium subsp. empetrifolium, and H. pruinatum species were determined with GC-MS/ FID. This is the first study on the antioxidant, anticholinesterase, anti-urease, antityrosinase, antielastase, and anticollagenase activities of these species. Also, in silico and in vitro enzyme in-hibitory activities of the major compounds in the essential oil samples of the species have been evaluated. In addition, the cytotoxic effects of the essential oils were determined by the MTT method.Results: According to GC-MS/ FID results, the major compounds were determined as caryophyllene oxide (16.76%) for H. triquetrifolium, alpha-pinene (21.67%) for H. empetrifolium subsp. empetrifolium, and germacrene D (22.47%) for H. pruinatum. Especially, H. pruinatum sample showed a high cytotoxic effect (IC50: 34.78 +/- 0.22 and 29.06 +/- 0.40 mu g/mL, respectively) on HT -29 and MCF-7 cell lines. It was determined that the same sample showed a promising inhibitory activity on acetyl (18.33 +/- 2.79, 36.48 +/- 2.40, and 56.97 +/- 0.94, respectively) and butyryl (71.63 +/- 2.78, 73.88 +/- 1.16, and 56.97 +/- 0.97, respectively) cholinesterase enzymes.Conclusion: Results of the in-vitro activity studies indicated that H. pruinatum essential oil could be used in the pharmaceuti-cal industry.Öğe 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, AndrewThe 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.Öğe Pyridine-containing chiral macrocycles for the enantioselective recognition of amino acid derivatives and their molecular dynamics simulations(Pergamon-Elsevier Science Ltd, 2010) Turgut, Yilmaz; Kocakaya, Safak OzhanTwo novel C-2-symmetric optically active pyridine-15-crown-5 type ligands containing lipophilic chains at the stereogenic centres, macrocycles 5 and 6, were prepared from (S)-1,2-propanediol and (S)-3-aryloxy-1,2-propanediol for the enantiomeric recognition of amino acid ester derivatives. These novel macrocycles have been shown to be strong complexing agents for primary organic ammonium salts (with K values of up to 1363.5 M-1, Delta G degrees of up to 17.86 kJ mol(-1) and a selectivity ratio of 80:20) by H-1 NMR titration method. These macrocyclic host exhibited enantioselective binding towards the L-enantiomer of phenylalanine methyl ester hydrochloride with K-L/K-D up to 8.57 in CDCl3 containing 0.25% CD3OD. Experimental results have been detailed with molecular dynamic calculations at atomic level concerning the molecular recognition and discrimination properties of a chiral pyridino-15-crown-5. The binding free energies were calculated as similar to-25 kJ mol(-1). The results indicated that the host binds and discriminates valine salts better than phenylalanine salts. The molecular dynamics, MM/PBSA calculations are consistent with the H-1 NMR results. (C) 2010 Elsevier Ltd. All rights reserved.Öğe Selective in vitro and in silico enzymes inhibitory activities of phenolic acids and flavonoids of food plants: Relations with oxidative stress(Elsevier Sci Ltd, 2020) Yener, Ismail; Kocakaya, Safak Ozhan; Ertas, Abdulselam; Erhan, Bahadir; Kaplaner, Erhan; Oral, Elif Varhan; Yilmaz-Ozden, TugbaIn this study, the inhibitory potentials of food originated 34 phenolic acids, and flavonoid compounds were screened against acetylcholinesterase, butyrylcholinesterase, urease, and tyrosinase enzymes. All compounds included in this study exhibited high antioxidant activity with an ignorable cytotoxic activity. In general, they also showed poor anti-urease and anti-tyrosinase activities. Compounds in aglycone form (quercetin, myricetin, chrysin, and luteolin) showed strong anticholinesterase activities. No relation was observed between the tested bioactivities except from the case that aglycone compounds exhibited a strong positive relationship between antioxidant activities and anticholinesterase activity. Interestingly, there was a relation between the molecular weights of aglycone compounds and their anticholinesterase activities. The study showed that flavonoids with molecular mass of 250-320 g/mol have high potential of anticholinesterase activities and are valuable for future experiments on animals and humans. Potential inhibitory effects of these molecules on target proteins were investigated using docking and molecular dynamics calculations.Öğe Selective in-vitro Enzymes' Inhibitory Activities of Fingerprints Compounds of Salvia Species and Molecular Docking Simulations(Shaheed Beheshti Univ, Sch Pharmacy, 2020) Kocakaya, Safak Ozhan; Ertas, Abdulselam; Yener, Ismail; Ercan, Bahadir; Oral, Elif Varhan; Akdeniz, Mehmet; Kaplaner, ErhanRecently Nutrition and Food Chemistry researches have been focused on plants and their products or their secondary metabolites having anti-alzheimer, anti-cancer, anti-aging, and antioxidant properties. Among these plants Salvia L. (Lamiaceae) species come into prominence with their booster effects due to high antioxidant contents, which have over 900 species in the world and 98 in Turkey. Some Salvia species are already in use as herbal treatment of vessel stiffness, Dementia like problems and cancer. Recently some species of Salvia are of extensive research topic. In this study, inhibitory potentials of secondary metabolites, rosmarinic acid, salvigenin, salvianolic acid A and B, tanshinone I and IIA, cyrtotanshinone, dihydrotanshinone I, carnosic acid, carnosol, and danshensu sodium salt were investigated against acetylcholinesterase, butyrylcholinesterase, urease and tyrosinase enzymes both in-vitro and in slico in detail. Elevated inhibitory effects on acetyl-and butyryl-cholinesterase of dihydrotanshinone I (IC50: 1.50 +/- 0.02 and 0.50 +/- 0.01 mu g/mL, respectively), carnasol (IC50: 11.15 +/- 0.05 ve 3.92 +/- 0.03 mu g/mL) and carnosic acid (IC50: 31.83 +/- 0.65 ve 4.12 +/- 0.04 mu g/mL) were observed. Furthermore, all other secondary metabolites were active against butyrylcholinesterase. Anti-urease (42.41 +/- 0.85%) and anti-tyrosinase (39.82 +/- 1.16%) activities of tanshinone I were also observed. Potential inhibitory effects of these molecules on target proteins were investigated using DOCK and molecular dynamics calculations. Dock score analysis and Lipinski parameters were demonstrated that these ligands are potential inhibitors against relevant enzymes. Our findings suggest that Salvia species can be utilized as a ptential source of anti-alzheimer active compounds for designing novel products.Öğe Synthesis and crystal structure of a chiral lactam and three amino alcohols as potential protein tyrosine phosphates 1B inhibitors(Pergamon-Elsevier Science Ltd, 2017) Kocakaya, Safak Ozhan; Karakaplan, Mehmet; Scopelliti, RosarioChiral lactam 2 and three chiral 3-amino alcohols 3-5 have been synthesized and characterized by Sspectroscopic techniques. Regioselective ring opening reaction of chiral styrene oxide by an amine nucle-ophile was confirmed by X-ray diffraction data. Ligand 2-4 crystallizes in the tetragonal, orthorhombic and tetragonal crystal lattice system respectively. Ligands 2-6 have been used as potential inhibitors for protein tyrosine phosphatase 1B enzyme (PTP1B). The potential inhibitor effect of these molecules to the target protein was investigated by Dock and molecular dynamics calculations. Dock score analysis and Lipinski parameters suggested that ligands 1,2,4-6 are potential inhibitors towards PTP1B, thus indicating that the residues Arg24, Arg254 and Met258, Asp29 in the second active site of PTP1B are essential for the high selectivity of inhibitors. The results indicate that the polar hydrogen bonding interacts with Asp29, Gln102, and the amino acid residues of PTP1B are responsible for governing inhibitory potency of ligands 1-6. (C) 2017 Elsevier Ltd. All rights reserved.Öğe 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, NecmettinThe 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.
