PubMed İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/397
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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 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: 1Citation - Scopus: 2Discovery of a C-S Lyase Inhibitor for the Prevention of Human Body Malodor Formation: Tannic Acid Inhibits the Thioalcohol Production in Staphylococcus Hominis(Springer, 2024-06-24) Fidan, Ozkan; Karipcin, Ayse Doga; Kose, Ayse Hamide; Anaz, Ayse; Demirsoy, Beyza Nur; Arslansoy, Nuriye; Mujwar, SomduttHuman body odor is a result of the bacterial biotransformation of odorless precursor molecules secreted by the underarm sweat glands. In the human axilla, Staphylococcus hominis is the predominant bacterial species responsible for the biotransformation process of the odorless precursor molecule into the malodorous 3M3SH by two enzymes, a dipeptidase and a specific C-S lyase. The current solutions for malodor, such as deodorants and antiperspirants are known to block the apocrine glands or disrupt the skin microbiota. Additionally, these chemicals endanger both the environment and human health, and their long-term use can influence the function of sweat glands. Therefore, there is a need for the development of alternative, environmentally friendly, and natural solutions for the prevention of human body malodor. In this study, a library of secondary metabolites from various plants was screened to inhibit the C-S lyase, which metabolizes the odorless precursor sweat molecules, through molecular docking and molecular dynamics (MD) simulation. In silico studies revealed that tannic acid had the strongest affinity towards C-S lyase and was stably maintained in the binding pocket of the enzyme during 100-ns MD simulation. We found in the in vitro biotransformation assays that 1 mM tannic acid not only exhibited a significant reduction in malodor formation but also had quite low growth inhibition in S. hominis, indicating the minimum inhibitory effect of tannic acid on the skin microflora. This study paved the way for the development of a promising natural C-S lyase inhibitor to eliminate human body odor and can be used as a natural deodorizing molecule after further in vivo analysis.