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Öğe BAZI ANTI·VI·RAL AJANLARIN I·NSAN TELOMERAZ ENZİMİ ÜZERI·NDEKI· I·NHI·BI·TÖR POTANSI·YELI·NI·N MOLEKÜLER KENETLENME VE MOLEKÜLER DI·NAMI·K SI·MÜLASYON ÇALIŞMALARI I·LE ARAŞTIRILMASI(Ankara Üniversitesi, 2024) Konyar, Dilan; Muhammed, Muhammed TılahunAmaç: Bu çalışmada, nükleozid ve non-nükleozid ters transkriptaz inhibitörü ilaçların, antikanser etki potansiyeli hesaplamalı yaklaşımlar kullanılarak araştırılmıştır. Bu amaçla, bu ilaçların telomeraz ters transkirptaz (TERT)'ın telomeraz temel N-terminal (TEN) alanına bağlanma potansiyeli araştırılmıştır. İlaçların TEN alanına bağlanma potansiyeli için moleküler yerleştirme çalışması yapılmıştır. Moleküler yerleştirme sonucu elde edilen protein-ilaç kompleksinin kararlılığı moleküler dinamik (MD) simülasyonu ile değerlendirilmiştir. Gereç ve Yöntem: TERT'in TEN alanı kristal yapısı için Protein Veri Bankası (PDB) kullanılmıştır. 2,2 Å çözünürlüğe sahip PDB kodu 2B2A kristal yapı kullanımıştır. Moleküler yerleştirme çalışması için AutoDock Vina programı kullanılmıştır. Kompleksler Biovia Discovery Studio kullanılarak görselleştirilmiştir. MD simülasyonu GROMACS 2020 kullanılarak gerçekleştirilmiştir. Hem kompleksler hem de serbest protein üzerinde 200 ns boyunca bir MD simülasyonu gerçekleştirilmiştir. Omurga protein ve moleküllerin, omurga yapısına göre RMSD (kök ortalama kare sapması), RMSF (kök ortalama kare dalgalanması) ve Rg (dönme yarıçapı), Qt Grace ile gösterilmiştir. Sonuç ve Tartışma: Moleküler yerleştirme çalışması sonucunda, Doravirin (bileşik 3), Etravirin (bileşik 6) ve Rilpivirin’in (bileşik 9) referans TERT inhibitörü BIBR1532'ye kıyasla TEN alanına daha yüksek bağlanma potansiyeli ile bağlandığını ortaya koymuştur. MD simülasyon çalışması ile, protein-Doravirin kompleksinin proteinin bağlanma cebindeki en yüksek stabiliteye sahip olduğu gösterilmiştir. Öte yandan, protein-Rilpivirin kompleksinin kararlı olmaması nedeniyle bağlanma cebinde kalmama ihtimali bulunmaktadır. Yapılan çalışma, Doravirin’in TEN’i inhibe edebileceğini göstermiştir. Bu nedenle, Doravirin'in TERT'in TEN alanını inhibe ederek antikanser potansiyel gösterebilme ihtimali nedeniyle Doravirin türevi yeni bileşiklerin tasarlanması ve sentezlenmesi düşünülmektedir.Öğe Design, Synthesis, and Biological Evaluation of Some Novel Retinoid Derivatives(Bentham Science Publ Ltd, 2024) Konyar, Dilan; Foto, Egemen; Foto, Fatma Zilifdar; Buyukbingol, Mehmet ErdemBackground As cancer stands as a significant global health concern, many heterocyclic compounds that are more effective in cancer cells than healthy cells are being investigated for their selective anticancer potentials. One such compound is fenretinide, a synthetic derivative of retinoic acid that has a broad spectrum of cytotoxic activity against primary tumor cells, cell lines, and/or xenografts of various cancers. In this context, bexarotene and its derivatives, synthesized from hybridization of the fenretinide, are expected to possess a potential anticancer activity.Objective The objective of the present study was to investigate the synthesis of novel amid-derived and bexarotene-based compounds, as well as to assess their cytotoxic effects in different cancer cell lines.Methods This study involved the synthesis of twelve novel retinoid derivatives (6-17) in a six-step process. The cytotoxic activities of these compounds were assessed against various cancer cell lines, such as A549 (human lung carcinoma), HeLa (human cervical cancer), MCF7 (human breast adenocarcinoma), and WiDr (human colon adenocarcinoma). The chemical structures of these compounds were elucidated through their elemental analysis, mass spectrometry (ESI+, ESI-), as well as 1H-NMR and 13C-NMR spectroscopic data.Results The obtained cell toxicity results indicated that compounds 6, 8, 11, 12, 13, 14, and 17 were found to exhibit the strongest cytotoxic activity in above mentioned cancer cell lines. The IC50 values for active compounds, 11 and 12, were determined as 2.38 mu M and 2.29 mu M, respectively. Remarkably, these compounds displayed higher cytotoxic activity in the WiDr cell line related to positive control, camptothecin (CPT). Moreover, compounds 14 and 17 demonstrated very similar level of cytotoxic activity to CPT, indicating their potential for antitumoral applications upon further studies.Conclusion While compounds 11, 12, 14, and 17 indicated a very comparable anticancer activity to CPT, compounds 6, 8, 11 and 12 showed more selective anticancer effect against cancer cells than non-cancerous cells. In accordance with the findings of the present study, they can be evaluated as primary candidates for further studies, specifically as RXR alpha-targeted anticancer agents.Öğe INVESTIGATION OF THE INHIBITORY POTENTIAL OF SOME ANTIVIRAL AGENTS ON HUMAN TELOMERASE BY MOLECULAR DOCKING AND MOLECULAR DYNAMICS SIMULATION STUDIES(University of Ankara, 2024) Konyar, Dilan; Muhammed, Muhammed TilahunObjective: This study investigated the anticancer effects of nucleoside and non-nucleoside reverse transcriptase inhibitors drugs by computational methods. The study aimed to evaluate the binding capacity of these drugs on the telomerase essential N-terminal (TEN) domain of telomerase reverse transcriptase (TERT). Molecular docking was used to assess the drugs' binding potential to the TEN domain. The stability of the protein-drug combination obtained from the docking method was assessed using molecular dynamics (MD) simulation. Material and Method: The TEN domain of TERT's crystal structure was obtained from the Protein Data Bank (PDB). The crystal structure identified by the PDB code 2B2A has a resolution of 2.2 Å. The molecular docking was performed using AutoDock Vina. The complexes were visualized using Biovia Discovery Studio. The MD simulation was conducted using GROMACS 2020 as indicated. An MD simulation was conducted for 200 ns on both the complexes and the free protein. The RMSD (root mean square deviation) of the backbone protein and the molecules in relation to the backbone protein, RMSF (root mean square fluctuation), and Rg (radius of gyration) were shown via Qt Grace. Result and Discussion: Doravirine, Etravirine, Rilpivirine showed higher binding affinity to the TEN domain compared to the reference TERT inhibitor, BIBR1532, based on the docking investigation. The MD simulation analysis showed that the protein-Doravirine complex had the highest stability in remaining within the protein's binding pocket. On the contrary, the protein-Rilpivirine complex decreased stability, potentially causing the ligand to not to stay within the binding site. Doravirine was found to inhibit the TEN domain in the computational study. Therefore, the design and synthesis of novel doravirin derivatives is being considered because of the potential anticancer activity of doravirin in inhibiting the TEN domain of TERT. © 2024 University of Ankara. All rights reserved.Öğe Molecular docking studies of cox inhibitors on wild-type ras(Ankara Üniversitesi Eczacılık Fakültesi, 2022) Konyar, Dilan; Okur, Hayati; Arslan, ZehraObjective: In addition to its role in the formation mechanism of inflammation, the binding potential of COX inhibitors, which can inhibit tumorogenesis by induce apoptosis, has been explored by molecular docking studies on wild-type RAS enzyme. Material and Method: KRAS enzyme (PDB ID: 4OBE), which consists is obtained by the x-ray crystallization method, was chosed considering the resolution. The 2D structures of ligand molecules were drawn in the ChemDraw 19.1. The MOE 2020 program was used to form the docking studies. Result and Discussion: As a result of docking studies, it has been understood that the presence of aromatic structures in 3a and 3b ligand molecules is critical for ligand-receptor interaction. it has been understood that there must be a certain distance between the carbonyl group and the nonpolar part of the molecule for the molecule to bind to the receptor site with a high affinity. In the following stages, more effective anticancer drug molecules can be obtained by design molecules with an appropriate diameter and length, having functional groups containing the suitable electron donor or acceptor.Öğe Some heterocycles connected to substituted piperazine by 1,3,4-oxadiazole linker: Design, synthesis, anticholinesterase and antioxidant activity(Elsevier B.V., 2025) Kurt, Zuhal Kılıç; Konyar, Dilan; Okur, Hayati; Kaplan, Alevcan; Boǧa, MehmetAD is a multifactorial neurodegenerative disease that has caused morbidity and mortality on a global scale. Currently, there are only a few drugs used in the treatment of AD. Although many compounds that aim at new targets have reached clinical trials, none have been approved. However, discovering efficient drugs for AD treatment is one of the biggest challenges for pharmaceutical research and requires strong support. In this paper, we aim to design a series of indole, benzothiophene, and thiophene bearing 1,3,4-oxadiazole linker to the piperazine basic center and evaluate for their antioxidant and inhibitory activity against both cholinesterase enzymes. Among the compounds, 6a, 7b, and 8b exhibited moderate cationic radical scavenging activities with IC50 values ranging from 20.39 to 30.10 μM. The inhibitory activity results revealed that compounds 5c (IC50 for AChE = 53.91 μM and for BChE = 55.81 μM) and 6c (IC50 for AChE = 54.42 μM and BChE = 45.82 μM) bearing 2-fluorophenyl piperazine moiety showed both AChE and BChE inhibition with moderate IC50 values. To explore the binding properties of the target compounds into the active site of the enzyme, a molecular docking study was carried out using MOE software. The docking study showed that compound 6c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE/BChE and formed important interactions with key residues. Moreover, theoretical physicochemical properties of the best active compound 6c were calculated by the SwissADME web service. It obeyed Lipinski's rule of five and had high GI absorption (gastrointestinal absorption) and good permeating to the blood-brain barrier (BBB). The compound 6c can be considered a promising compound and provides us directions for further research of anti-AD agent development.
