Browsing by Author "Djikic, Teodora"

Now showing 1 - 7 of 7

Citation Count: 51
Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies
(Frontiers Media Sa, 2016) Yelekçi, Kemal; Mavridis, Lazaros; Djikic, Teodora; Vucicevic, Jelica; Agbaba, Danica; Yelekçi, Kemal; Mitchell, John B. O.
The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer's disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug discovery programs. A probabilistic method, the ParzenRosenblatt Window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands targeting AChE/MAO-A/MAO-B and also D-1-R/D-2-R/5-HT2A-R/H-3-R are promising novel drug candidates with improved efficacy and beneficial neuroleptic and procognitive activities in treatment of Alzheimer's and related neurodegenerative diseases. Structural information for drug targets permits docking and virtual screening and exploration of the molecular determinants of binding, hence facilitating the design of multi-targeted drugs. The crystal structures and models of enzymes of the monoaminergic and cholinergic systems have been used to investigate the structural origins of target selectivity and to identify molecular determinants, in order to design MTDLs.
Citation Count: 7
Human dopamine transporter: the first implementation of a combined in silico/in vitro approach revealing the substrate and inhibitor specificities
(Taylor & Francis Inc, 2019) Djikic, Teodora; Marti, Yasmina; Spyrakis, Francesca; Lau, Thorsten; Benedetti, Paolo; Davey, Gavin; Schloss, Patrick; Yelekçi, Kemal
Parkinson's disease (PD) is characterized by the loss of dopamine-generating neurons in the substantia nigra and corpus striatum. Current treatments alleviate PD symptoms rather than exerting neuroprotective effect on dopaminergic neurons. New drugs targeting the dopaminergic neurons by specific uptake through the human dopamine transporter (hDAT) could represent a viable strategy for establishing selective neuroprotection. Molecules able to increase the bioactive amount of extracellular dopamine thereby enhancing and compensating a loss of dopaminergic neurotransmission and to exert neuroprotective response because of their accumulation in the cytoplasm are required. By means of homology modeling molecular docking and molecular dynamics simulations we have generated 3D structure models of hDAT in complex with substrate and inhibitors. Our results clearly reveal differences in binding affinity of these compounds to the hDAT in the open and closed conformations critical for future drug design. The established in silico approach allowed the identification of promising substrate compounds that were subsequently analyzed for their efficiency in inhibiting hDAT-dependent fluorescent substrate uptake through in vitro live cell imaging experiments. Taken together our work presents the first implementation of a combined in silico/in vitro approach enabling the selection of promising dopaminergic neuron-specific substrates.
Citation Count: 0
In Silico Modeling of Dopamine Transporter and Design of Novel Neuroprotective Agents
(Amer Chemical Soc, 2016) Yelekçi, Kemal; Yelekci, Kemal
[Abstract Not Available]
Citation Count: 20
Synthesis and Screening of Human Monoamine Oxidase-A Inhibitor Effect of New 2-Pyrazoline and Hydrazone Derivatives
(Wiley-VCH Verlag GmbH, 2015) Yelekçi, Kemal; Baysal, İpek; Yabanoğlu-Çiftçi, Samiye; Djikic, Teodora; Yelekçi, Kemal; Uçar, Gülberk; Ertan, Rahmiye
A group of 35-diaryl-2-pyrazoline and hydrazone derivatives was prepared via the reaction of various chalcones with hydrazide compounds in ethanol. Twenty original compounds were synthesized. Ten of these original compounds have a pyrazoline structure nine of these original compounds have a hydrazone structure and one of these original compounds has a chalcone structure. Structural elucidation of the compounds was performed by IR H-1 NMR C-13 NMR mass spectral data and elemental analyses. These compounds were tested for their inhibitory activities toward the A and B isoforms of human monoamine oxidase (MAO). Except for 3k and 6c all compounds were found to be competitive reversible and selective inhibitors for either one of the isoforms (hMAO-A or MAO-B). Compounds 3k and 6c were found to be competitive reversible but non-selective MAO inhibitors. Compound 6h showed hMAO-B inhibitory activity whereas the others potently inhibited hMAO-A. Compound 5c showed higher selectivity than the standard drug moclobemide. According to the experimental K-i values compounds 6i 6d and 6a exhibited the highest inhibitory activity toward hMAO-A. The AutoDock 4.2 program was employed to perform automated molecular docking. The calculated results obtained computationally were in good agreement with the experimental values.
Citation Count: 20
Synthesis anticancer activity and molecular modeling of etodolac-thioether derivatives as potent methionine aminopeptidase (type II) inhibitors
(Wiley, 2018) Yelekçi, Kemal; Çevik, Ozge; Yelekçi, Kemal; Djikic, Teodora; Küçükgüzel, Şükriye Güniz
A series of (RS)-1-{[5-(substituted)sulfanyl-4-substituted-4H-124-triazole-3-yl]methyl}-18-diethyl-1349-tetrahydropyrano[34-b]indoles (5a-v) were designed and synthesized using a five-step synthetic protocol that involves substituted benzyl chlorides and (RS)-5-[(18-diethyl-1349-tetrahydropyrano[34-b]indole-1-yl)methyl]-4-substituted-24-dihydro-3H-124-triazole-3-thiones in the final step. The synthesized derivatives were evaluated for cytotoxicity and anticancer activity in vitro using the MTT (3-(45-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide) colorimetric method against VERO HEPG2 (human hepatocellular liver carcinoma) SKOV3 (ovarian carcinoma) MCF7 (human breast adenocarcinoma) PC3 and DU145 (prostate carcinoma) cells at 10(-5)M (10M) for 24h. Compounds 5d and 5h showed the best biological potency against the SKOV3 cancer cell line (IC50=7.22 and 5.10M respectively) and did not display cytotoxicity toward VERO cells compared to etodolac. Compounds 5k 5s and 5v showed the most potent biological activity against the PC3 cancer cell line (IC50=8.18 3.10 and 4.00M respectively) and did not display cytotoxicity. Moreover these compounds were evaluated for caspase-3 -9 and -8 protein expression and activation in the apoptosis pathway for 6 12 and 24h which play a key role in the treatment of cancer. In this study we also investigated the apoptotic mechanism and molecular modeling of compounds 5k and 5v on the methionine aminopeptidase (type II) enzyme active site in order to get insights into the binding mode and energy.
Citation Count: 21
Synthesis Molecular Docking and Anticancer Activity of Diflunisal Derivatives as Cyclooxygenase Enzyme Inhibitors
(MDPI, 2018) Yelekçi, Kemal; Djikic, Teodora; Hayal, Taha Bartu; Turkel, Nezaket; Yelekçi, Kemal; Sahin, Fikrettin; Küçükgüzel, Şükriye Güniz
Cyclooxygenase enzymes play a vital role in inflammatory pathways in the human body. Apart from their relation with inflammation the additional involvement of COX-2 enzyme with cancer activity was recently discovered. In some cancer types the level of COX-2 enzyme is increased indicating that this enzyme could be a suitable target for cancer therapy. Based on these findings we have synthesized some new diflunisal thiosemicarbazides and 124-triazoles and tested them against androgen-independent prostate adenocarcinoma (PC-3) colon carcinoma (HCT-116) human breast cancer (T47D) breast carcinoma (MCF7) and human embryonic kidney (HEK-293) cell lines. Specifically the diflunisal and thiosemicarbazide functionality are combined during the synthesis of original compounds anticipating a potency enhancement. Compounds 6 10 15 and 16 did not show cytotoxic effects for the HEK293 cell line. Among them compounds 15 and 16 demonstrated anticancer activity for the breast cancer cell line T47D whereas compounds 6 and 10 which are thiosemicarbazide derivatives displayed anti-tumourigenic activity against the PC-3 cell line consistent with the literature. However no activity was observed for the HCT-116 cancer cell line with the tested thiosemicarbazide derivatives. Only compound 16 displayed activity against the HCT-116 cell line. Therefore it was speculated that the diflunisal and thiosemicarbazide functionalities potentiate anticancer activity on prostate cancer and the thiosemicarbazide functionality decreases the anticancer activity of diflunisal on colon cancer cell lines. In order to gain insight into the anticancer activity and COX-2 inhibition molecular docking studies were carried out for COX-1 and COX-2 enzymes utilizing the newly synthesized compounds 15 and 16. Both 15 and 16 showed high selectivity and affinity toward COX-2 isozyme over COX-1 which is in agreement with the experimental results.
Citation Count: 5
Synthesis Molecular Modelling and Antibacterial Activity Against Helicobacter pylori of Novel Diflunisal Derivatives as Urease Enzyme Inhibitors
(Bentham Science Publ Ltd, 2019) Yelekçi, Kemal; Djikic, Teodora; Kalaycı, Sadık; Yelekçi, Kemal; Şahin, Fikrettin; Küçükgüzel, Şükriye Güniz
Background: The main factor for the prolongation of the ulcer treatment in the gastrointestinal system would be Helicobacter pylori infection which can possibly lead to gastrointestinal cancer. Triple therapy is the treatment of choice by today's standards. However observed resistance among the bacterial strains can make the situation even worse. Therefore there is a need to discover new targeted antibacterial therapy in order to make success in the eradication of H. pylori infections. Methods: The targeted therapy rule is to identify the related macromolecules that are responsible for the survival of the bacteria. Thus 2-[(2'4'-difluoro-4-hydroxybiphenyl-3-yl)carbonyl]-N-( substituted)hydrazinocarbothioamide (3-13) and 5-(2'4'-difluoro-4-hydroxybiphenyl-3-yl)-4-( substituted)-24-dihydro-3H-124-triazole-3-thiones (14-17) were synthesized and evaluated for antibacterial activity in vitro against H. pylori. Results: All of the tested compounds showed remarkable antibacterial activity compared to the standard drugs (Ornidazole Metronidazole Nitrimidazin and Clarithromycin). Compounds 4 and 13 showed activity as 2 mu g/ml MIC value. Conclusion: In addition we have investigated binding modes and energy of the compounds 4 and 13 on urease enzyme active by using the molecular docking tools.