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Now showing 1 - 10 of 77
  • PublicationMetadata only
    Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain.
    (2012-10-01) THOMPSON, AJ; de, Graaf; Akdemir, ATİLLA; de, Esch; KOOISTRA, AJ; EDINK, E; LUMMIS, SC; AKDEMİR, ATİLLA
    A hierarchical in silico screening procedure using the crystal structure of an agonist bound chimeric α7/Ls-AChBP protein was successfully applied to both proprietary and commercial databases containing drug-like molecules. An overall hit rate of 26% (pK(i) ≥5.0) was obtained, with an even better hit rate of 35% for the commercial compound collection. Structurally novel and diverse ligands were identified. Binding studies with [(3)H]epibatidine on chimeric α7/5-HT(3) receptors yielded submicromolar inhibition constants for identified hits. Compared to a previous screening procedure that utilized the wild type Ls-AChBP crystal structure, the current study shows that the recently obtained α7/Ls-AChBP chimeric protein crystal structure is a better template for the identification of novel α7 receptor ligands.
  • PublicationMetadata only
    Fragment growing induces conformational changes in acetylcholine-binding protein: a structural and thermodynamic analysis.
    (2011-04-13T00:00:00Z) SIXMA, TK; SMIT, AB; Akdemir, ATİLLA; de, Esch; LEURS, R; van, Muijlwijk-Koezen; van, Nierop; JANSSEN, E; van, Elk; ZUIDERVELD, O; NAHAR, T; RETRA, K; RUCKTOOA, P; EDINK, E; AKDEMİR, ATİLLA
  • PublicationMetadata only
    Abietane diterpenoids as butyrylcholinesterase inhibitors from Salvia species
    (2012-08-01) Topcu, GÜLAÇTI; Akdemir, ATİLLA; Öztürk, Mahmut Serdar; Boğa, Miray; Kola, U.; TOPÇU, GÜLAÇTI; AKDEMİR, ATİLLA
  • PublicationOpen Access
    Thiosemicarbazide-Substituted Coumarins as Selective Inhibitors of the Tumor Associated Human Carbonic Anhydrases IX and XII
    (2022-07-01T00:00:00Z) GÜMÜŞ PALABIYIK, ARZU; Bozdag, Murat; AKDEMİR, ATİLLA; Angeli, Andrea; Selleri, Silvia; Carta, Fabrizio; Supuran, Claudiu T.; AKDEMİR, ATİLLA
    A novel series of thiosemicarbazide-substituted coumarins was synthesized and the inhibitory effects against four physiologically relevant carbonic anhydrase isoforms I, II, IX and XII showed selective activities on the tumor-associated IX and XII isozymes. Molecular modeling studies on selected compounds 14a and 22a were performed. The binding modes of such compounds were determined assuming their enzymatically active structures (i.e., cinnamic acid) in the thermodynamically favored, and not previously explored, E geometry. Molecular modelling suggests multiple interactions within the enzymatic cavity and may explain the high potency and selectivity reported for the hCAs IX and XII.
  • PublicationMetadata only
    rac- and meso-Cyclohexanoids: Their alpha-, beta-glycosidases, antibacterial, antifungal activities, and molecular docking studies
    (2020-01-10T00:00:00Z) Karakilic, Emel; Baran, Sule; Ogutcu, Hatice; AKDEMİR, ATİLLA; Baran, Arif; AKDEMİR, ATİLLA
    An efficient and versatile synthesis method has been postulated for hydroxymethylated rac- and meso-cyclohexanoid derivatives. The synthesis of these stereoisomers was achieved easily with traditional methods using hexahydroisobenzofuran 6, prepared from commercially available cis-hydrophthalic anhydride. The study, involving diastereoselective epoxidation and cis-hydroxylation, was conducted to obtain epoxy-, cis-, and trans-diol-furans 7, 8, and 9. After sulfamic acid-catalyzed ring-opening reaction of the epoxide and furan rings, rac- and meso-tetraacetates 14, 15, and 16 were afforded. Hydrolysis of acetate groups with ammonia in absolute methanol yielded the desired tetrols rac-17, meso-18, and meso-19. All structures, after purification by chromatographic methods and elucidation by spectral techniques, were screened against alpha- and beta-glucosidases. Compounds 7, 8, 10, 17, 18, and 19 were also evaluated for their antibacterial and antifungal activity against some selected synthesized compounds with varying degrees of inhibitory effects on the growth of different pathogenic microorganisms by the well-diffusion method. In addition, Saccharomyces cerevisiae alpha-glucosidase molecular modeling studies were performed for all rac- and meso-compounds 7, 8, 10, 17, 18, and 19.
  • PublicationMetadata only
    Design and synthesis of new heterocyclic compounds containing 5-[(1H-1,2,4-triazol-1-yl)methyl]-3H-1,2,4-triazole-3-thione structure as potent hEGFR inhibitors
    (2023-01-01) KOLCUOĞLU Y.; BEKİRCAN O.; Fazli H.; Sahin E.; TÜRE A.; AKDEMİR A.; Hamarat Sanlier S.; AKDEMİR, ATİLLA
    © 2023 Informa UK Limited, trading as Taylor & Francis Group.EGFR is one of the important mediators of the signaling cascade that determines key roles in various biological processes such as growth, differentiation, metabolism and apoptosis in the cell in response to external and internal stimuli. In recent years, it has been proven that although this enzyme activity is tightly regulated in normal cells, if the enzyme activity cannot be controlled, it can lead to malignancy. EGFR is also considered a prominent macromolecule in targeted cancer chemotherapy. For this purpose, a comprehensive modeling studies were conducted against EGFR protein and novel molecules containing 5-[(1H-1,2,4-triazol-1-yl)methyl]-3H-1,2,4-triazole-3-thione structure were suggested to be synthesized. Among the synthesized molecules, compounds 7c, 8c, 8f and 8g were determined to have significant IC50 values. Compound 8g was found to have the IC50 value closest to the very well-known EGFR inhibitor Gefitinib with its noncompetitive inhibition form. K i value of compound 8g was calculated as 0.00232 µM. Communicated by Ramaswamy H. Sarma.
  • PublicationOpen Access
    The neutralization effect of montelukaston SARS-CoV-2 is shown by multiscale in silicosimulations and combined in vitro studies
    (2021-10-19T00:00:00Z) Durdagi, Serdar; Avsar, Timucin; Orhan, Muge Didem; Serhatli, Muge; Balcioglu, Bertan Koray; Ozturk, Hasan Umit; Kayabolen, Alisan; Cetin, Yuksel; Aydinlik, Seyma; Bagci-Onder, Tugba; Tekin, Saban; Demirci, Hasan; Guzel, Mustafa; Akdemir, ATİLLA; Calis, Seyma; Oktay, Lalehan; Tolu, Ilayda; Butun, Yasar Enes; Erdemoglu, Ece; Olkan, Alpsu; Tokay, Nurettin; Işık, Şeyma; Ozcan, Aysenur; Acar, Elif; Buyukkilic, Sehriban; Yumak, Yesim; AKDEMİR, ATİLLA
    Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real-time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of montelukast both on the main protease enzyme inhibition and virus entry into the host cell (spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with montelukast for 20 h on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and, if its effect is proved in clinical phase studies, it should be used against coronavirus disease 2019 (COVID-19).
  • PublicationMetadata only
    A novel library of saccharin and acesulfame derivatives as potent and selective inhibitors of carbonic anhydrase IX and XII isoforms.
  • PublicationMetadata only
    Acetylcholine binding protein (AChBP) as template for hierarchical in silico screening procedures to identify structurally novel ligands for the nicotinic receptors.
    (2011-10-15T00:00:00Z) RUCKTOOA, P; JONGEJAN, A; Akdemir, ATİLLA; de, Esch; de, Graaf; LEURS, R; SMIT, AB; BERTRAND, D; SIXMA, TK; BERTRAND, S; ELK, RV; AKDEMİR, ATİLLA