Person: AKDEMİR, ATİLLA
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Publication Metadata 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, ATİLLAA 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.Publication Open 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, ATİLLAA 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.Publication Metadata 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.Publication Open 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, ATİLLASmall 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).Publication Metadata only Dithiocarbamates and dithiocarbonates containing 6-nitrosaccharin scaffold: Synthesis, antimycobacterial activity and in silico target prediction using ensemble docking-based reverse virtual screening(2022-12-01) Trawally M.; Demir Yazıcı K.; Dingiş Birgül S. İ.; Kaya K.; Akdemir A.; Güzel Akdemir Ö.; DİNGİŞ BİRGÜL, SERAP İPEK; AKDEMİR, ATİLLAPublication Metadata only İlaç Tasarımı: Hedef Protein ile Etkileşimin Optimizasyonu(Nobel Tıp Kitapevi, 2021-01-01) Güzel Akdemir Ö.; Akdemir A.; AKDEMİR, ATİLLAPublication Metadata only Exploring new Probenecid-based carbonic anhydrase inhibitors: Synthesis, biological evaluation and docking studies.(2015-09-01) MOLLICA, A; COSTANTE, R; Akdemir, ATİLLA; CARRADORI, S; STEFANUCCI, A; MACEDONIO, G; CERUSO, M; SUPURAN, CT; AKDEMİR, ATİLLAPublication Open Access Novel thiazolidinone-containing compounds, without the well-known sulphonamide zinc-binding group acting as human carbonic anhydrase IX inhibitors.(2018-12-01) DEMIR, K; Akdemir, ATİLLA; ANGELI, A; GÜZEL-AKDEMIR, Ö; SUPURAN, CT; AKDEMİR, ATİLLAA small collection of 26 structurally novel thiazolidinone-containing compounds, without the well-known sulphonamide zinc-binding group, were synthesised and tested in enzyme inhibition assays against the tumour-associated hCA IX enzyme. Inhibition constants in the lower micromolar region (KI < 25 lM) have been measured for 17 of the 26 compounds. Even though the KI values are relatively weak, the fact that they do not contain a sulphonamide moiety suggests that these compounds do not interact with the active site zinc ion. Therefore, docking studies and molecular dynamics simulations have been performed to suggest binding poses for these structurally novel inhibitors.Publication Metadata only Computer Aided Design and Synthesis of New Ursane Triterpenoids with Nuclear Factor Kappa B Inhibition Effect(2019-12-19) Şenol, Halil; Akdemir, Atilla; Topçu, Gülaçtı; ŞENOL, HALIL; AKDEMİR, ATİLLA; TOPÇU, GÜLAÇTIPublication Open Access Fibrate-based N-acylsulphonamides targeting carbonic anhydrases: synthesis, biochemical evaluation, and docking studies.(2019-12-01) GIAMPIETRO, L; AMMAZZALORSO, A; CARRADORI, S; ANGELI, A; De, Filippis; FANTACUZZI, M; MACCALLINI, C; Akdemir, ATİLLA; SUPURAN, CT; AMOROSO, R; AKDEMİR, ATİLLAA large library of fibrate-based N-acylsulphonamides was designed, synthesised, and fully characterised in order to propose them as zinc binders for the inhibition of human carbonic anhydrase (hCA) enzymatic activity. Synthesised compounds were tested against four hCAs (I, II, IX, and XII) revealing a promising submicromolar inhibitory activity characterised by an isozyme selectivity pattern. Structural modifications explored within this scaffold are: presence of an aryl ring on the sulphonamide, p-substitution of this aryl ring, benzothiazole or benzophenone as core nuclei, and an n-propyl chain or a geminal dimethyl at Ca carbon. Biological results fitted well with molecular modelling analyses, revealing a putative direct interaction with the zinc ion in the active site of hCA I, II and IX. These findings supported the exploration of less investigated secondary sulphonamides as potential hCA inhibitors.