Scopus İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/395
Browse
6 results
Search Results
Article Identification of Potential Dual HDAC6 and HSP90 Inhibitors for the Treatment of Cancer Using Molecular Docking, Molecular Dynamics and MM/PBSA Studies: A Comprehensive In Silico Study(Bentham Science Publ Ltd, 2026) Yucel, Muhsin Samet; Akcok, IsmailBackground Histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) are crucial therapeutic targets in cancer research with their interconnected roles in regulating protein homeostasis and cellular processes. The interaction of these proteins within the cytosolic complex plays a critical role in regulating cancer cell survival and progression. Notably, current studies highlight that the simultaneous inhibition of HDAC6 and Hsp90 can produce synergistic effects and offer a promising therapeutic potential for combating malignant cancers.Objective The objective of this study was to explore potential compounds that can inhibit both HDAC6 and Hsp90 proteins.Methods In this study, a number of in-silico computational techniques were employed. A total of 791 molecules, sharing at least 30% similarity with previously identified four HDAC inhibitors, were obtained from the ZINC15 database and subjected to docking on HDAC6 and Hsp90 proteins. The top eight ligands demonstrating the best binding scores against both targets, with panobinostat and ganetespib serving as reference compounds for HDAC6 and Hsp90, respectively, were selected for further analysis. Subsequently, ADME prediction and molecular dynamics simulations were conducted on the selected ligands.Results A detailed molecular docking, molecular dynamics simulations and ADME studies have revealed that ZINC27653366 exhibited the highest inhibitory potential against both Hsp90 and HDAC6 target proteins, making it the most promising inhibitor.Conclusion In conclusion, although additional in vitro and in vivo studies are required for the validation, in silico evaluation of ZINC27653366 may position it as a promising candidate for the treatment of different types of cancers.Article A Small Indole Derivative Isolated From Caper (Capparis Ovata) as an Inducer of P53-Mediated Apoptosis in Prostate Cancer: Comprehensive In Vitro and In Silico Studies(Wiley, 2025-12-31) Acar, Ozden Ozgun; Gazioglu, Isil; Oruc, Hatice; Kale, Elif; Senol, Halil; Topcu, Gulacti; Sen, AlaattinNatural products with stunning chemical diversity have been extensively researched for their anticancer potential for more than fifty years. This study aimed to determine the effect of indole derivative 1H-indole-2-hydroxy-3-carboxylic acid (IHCA), isolated as a novel alkaloid from Capparis ovata, on selected tumor suppressor, apoptotic, and cell cycle regulatory genes, which are known to be important in cancer pathophysiology, on Caco-2 and LNCaP cells in comparison with Taxol. The molecular mechanism of IHCA's anticancer activity is essentially undefined. Different concentrations of IHCA increased the expression levels of apoptosis-related genes, including BCL-2 and TNF-alpha. In addition, the tumor suppressor genes PTEN, P53, and RB were increased in LNCaP and Caco-2 cells. KRAS, an oncogenic gene, was significantly downregulated by IHCA in LNCaP cells. Western blot results showed that the protein expression levels of P53 and PTEN in LNCaP cells were increased when treated with IHCA, whereas CDK4 and TNF-alpha were decreased. Finally, IHCA and doxorubicin significantly increased P53-driven luciferase activity compared to the control. The results strongly suggest that the novel natural compound IHCA has an anticancer effect involving the regulation of the P53 gene and its networks in vitro. The molecular docking and MD simulation analyses reveal that IHCA exhibits superior binding potential to the MDM2 protein compared to Nutlin-3a. MD simulations further confirm that IHCA maintains a more stable and consistent interaction with MDM2, as indicated by lower RMSD values and reduced ligand fluctuation. These results highlight IHCA's potential as a more effective MDM2 inhibitor, suggesting its promise as a lead compound for anticancer drug development.Clinical Trial Registration: Not applicable.Article Citation - WoS: 1Citation - Scopus: 1Interaction of Inula Viscosa (L.) Aiton with IBA1 via Rosmarinic Acid and Rutin: Insights from Computational Models and Biological Effects(Wiley-VCH verlag GmbH, 2025-10-29) Aktas Pepe, Nihan; Acar, Busra; Ceylan Ekiz, Yagmur; Senol, Ayse Merve; Semiz, Gurkan; Sen, Alaattin; Celik Turgut, GurbetInula viscosa (L.) Aiton is a traditional medicinal plant extensively utilized in Mediterranean nations for the treatment of rheumatic pain, inflammatory disorders, diabetes, anemia, and cancer. This study further explored its anti-inflammatory mechanisms through the highest components, chlorogenic acid, rosmarinic acid, and rutin, on the expression of the ionized calcium-binding adapter molecule 1 (Iba1) on monocyte-derived macrophage-like cells. Iba1 is known to contribute pathogenesis of diverse inflammatory diseases. HPLC analysis identified 13 major phenolic compounds, with rosmarinic acid, chlorogenic acid, and rutin as major components. The aqueous extract of the plant and its major components exhibited dose-dependent antiproliferative activity on pTHP-1, RAW264.7, and PCS-201-012 cells. Immunofluorescence staining revealed a significant reduction in Iba1 protein expression, which is associated with inflammation, at the high dose of I. viscosa and rutin. Molecular docking studies indicated that rosmarinic acid and rutin had the strongest predicted interactions with Iba1, with docking scores of -12.403 and -12.301 kcal/mol and MM/GBSA binding energies of -64.47 and -84.20 kcal/mol, respectively. I. visoca and its major components were observed to significantly suppress iNOS activity in LPS-stimulated cells; these findings were also supported by RT-PCR results. Treatment with the high dose of I. viscosa resulted in 9.45% necrotic cells and caused cell cycle arrest in the S phase (59.2 +/- 5.23%). This suggests that it may potentially reduce the proliferation of activated macrophages. In the fibroblast migration assays, the relative wound closure rate was found to be significant 27.06 +/- 18.09% at the low dose of I. viscosa and 31.59 +/- 22.42% at the high dose of I. viscosa. Although the relatively low wound closure rate limits tissue repair, it may benefit chronic wounds and fibrosis by suppressing excessive cell proliferation and inflammation. These results suggest that I. viscosa is a promising natural source of bioactive compounds with potential applications in anti-inflammatory drug development.Article Citation - Scopus: 1Possible Drug-Drug Interactions Between Mesalamine and Tricyclic Antidepressants Through CYP2D6 Metabolism - in Silico and in Vitro Analyses(Georg Thieme Verlag, 2025-04-01) Ozen, Melek B.; Gazioğlu, Işil; Ozgun-Acar, Özden; Guner, Hüseyin; Semiz, Gürkan; Sen, Alaattin; Ozgun Acar, OzdenMesalamine (mesalazine, 5-aminosalicylic acid, 5-ASA) is an essential anti-inflammatory agent both used for therapy and as a remission control in patients with inflammatory bowel diseases (IBD) such as ulcerative colitis (UC). Tricyclic antidepressants (TCAs) are used to alleviate remaining symptoms in patients already receiving IBD therapy or with quiescent inflammation. The cytochrome P4502D6 enzyme is involved in the metabolism of TCAs. Hence, it is crucial to investigate the role of CYP2D6 in 5-ASA metabolism. Initially, in silico analysis involving the docking of 5-ASA to CYP2D6 and molecular dynamics simulations was conducted. Next, the rate of O-demethylation of a nonfluorescent probe 3-[2-(N,N-diethyl-N-methylammonium)-ethyl]-7-methoxy-4-methylcoumarin (AMMC) into a fluorescent metabolite AMHC (3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-hydroxy-4-methylcoumarin) was optimized with baculosomes co-expressing human CYP2D6 and human P450 oxidoreductase (hCPR) to monitor CYP2D6 activity in a microtiter plate assay. The apparent Km and Vmax were found to be 1.30 μM and 32.68 pmol/min/mg of protein for the O-demethylation of AMMC to AMHC, and the reaction was linear for 40 min. Then, nonselective inhibition of CYP2D6 activity with various concentrations of 5-ASA was detected. Finally, the conversion of AMMC to metabolites was analyzed by HPLC-ESI-MS/MS spectrometry, and none were identified. Thus, this study suggests that concurrent use of mesalamine with TCA may lead to adverse effects, and CYP2D6 genotyping should be routinely performed on these patients to eliminate possible threats. © 2025 Elsevier B.V., All rights reserved.Article Citation - WoS: 4Citation - Scopus: 4Evaluation of Selected Plant Phenolics Via Beta-Secretase Inhibition, Molecular Docking, and Gene Expression Related to Alzheimer's Disease(MDPI, 2024-10-28) Akyurek, Tugba Ucar; Orhan, Ilkay Erdogan; Deniz, F. Sezer Senol; Eren, Gokcen; Acar, Busra; Sen, Alaattin; Şenol Deniz, F. Sezer; Uçar Akyürek, TugbaBackground: The goal of the current study was to investigate the inhibitory activity of six phenolic compounds, i.e., rosmarinic acid, gallic acid, oleuropein, epigallocatechin gallate (EGCG), 3-hydroxytyrosol, and quercetin, against beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), also known as beta-secretase or memapsin 2, which is implicated in the pathogenesis of Alzheimer's disease (AD). Methods and Results: The inhibitory potential against BACE1, molecular docking simulations, as well as neurotoxicity and the effect on the AD-related gene expression of the selected phenolics were tested. BACE1 inhibitory activity was carried out using the ELISA microplate assay via fluorescence resonance energy transfer (FRET) technology. Molecular docking experiments were performed in the human BACE1 active site (PDB code: 2WJO). Neurotoxicity of the compounds was carried out in SH-SY5Y, a human neuroblastoma cell line, by the Alamar Blue method. A gene expression analysis of the compounds on fourteen genes linked to AD was conducted using the real-time polymerase chain reaction (RT-PCR) method. Rosmarinic acid, EGCG, oleuropein, and quercetin (also used as the reference) were able to inhibit BACE1 with their respective IC50 values 4.06 +/- 0.68, 1.62 +/- 0.12, 9.87 +/- 1.01, and 3.16 +/- 0.30 mM. The inhibitory compounds were observed to occupy the non-catalytic site of the BACE1. However, hydrogen bonds were found to be present between rosmarinic acid and EGCG and aspartic amino acid D228 in the catalytic site. Oleuropein and quercetin effectively suppressed the expression of PSEN, APOE, and CLU, which are recognized to be linked to the pathogenesis of AD. Conclusions: The outcomes of the work bring quercetin, EGCG, and rosmarinic acid to the forefront as promising BACE1 inhibitors.Article Discovery of New Candidates Targeting the SH2 Domains of Spleen Tyrosine Kinase (Syk) Through in Silico Studies(Wiley-VCH Verlag GmbH, 2025-06) Sansacar, Merve; Sari, Ceyhun; Yucel, Muhsin Samet; Akcok, Emel Basak Gencer; Akcok, Ismail; Gencer Akçok, Emel BaşakSrc homology 2 (SH2) domains have become an increasingly popular candidate for researchers to search for novel therapeutics to target different diseases. Spleen tyrosine kinase (Syk) is one of the proteins with two SH2 domains that has a role in the pathogenesis of many diseases. Here, we report the discovery of a promising natural product (NP) inhibitor that targets the N-terminal SH2 (N-SH2) and C-terminal SH2 (C-SH2) domains of Syk simultaneously, through structure-based drug discovery approach. Molecular docking studies, followed by molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations, were utilized to reveal the interactions between NPs from "the COlleCtion of Open NatUral producTs (COCONUT)" database and Syk enzyme. Five natural products that have lowest Scoring and Minimization with AutoDock Vina (SMINA) scores against both SH2 domains of Syk were selected for further studies and compound CNP0265345 has the best binding free energies toward both C-SH2 and N-SH2 of Syk enzyme with -44.54 and -55.98 kcal/mol, respectively. Drug-likeness properties, absorption, distribution, metabolism, and excretion (ADME) and carcinogenicity predictions were also studied. In conclusion, our work highlights a novel drug candidate to target the Syk enzyme of SH2 domains using in silico methods.