Demir, Yeliz; Ceylan, Hamid; Yeşilkent, Esra Nur; Kizir, Duygu; Karaman, Melike; Türkeş, Cüneyt; Beydemir, Şükrü

Doxorubicin (DOX) is a potent chemotherapeutic agent whose dose-dependent cardiotoxicity is associated with oxidative stress, inflammation, and enzymatic dysfunction. This study evaluates the cardioprotective potential of esculetin, a natural coumarin derivative, against DOX-induced cardiac injury in rats. Forty-eight male Sprague-Dawley rats were divided into six groups, including control, DOX, esculetin (50 and 100 mg/kg), and combination treatments. DOX markedly altered the expression of oxidative stress-related genes (Ache, Ar, Sord upregulated; Pon1, Gst downregulated) and impaired enzyme activities, accompanied by increased malondialdehyde and depleted glutathione levels. Esculetin administration, particularly at 100 mg/kg, reversed these molecular and biochemical disturbances, restoring antioxidant defense and normalizing gene expression. Molecular docking revealed strong binding interactions of esculetin with the active sites of key enzymes including AR, SORD, AChE, GST, and PON1, supporting its regulatory role. These findings suggest that esculetin exerts multi-targeted protective effects and may serve as a promising candidate for mitigating chemotherapy-induced cardiotoxicity. Further research is warranted to explore its integration into clinical cardioprotective strategies.

Güzel, Yahya; Karakaya, Sevcan; Wang, Lichang; Türkmenoğlu, Burçin; Kızılcan, Dilek Şeyma

The understanding of the interaction mechanism between ligands and receptors depends on the performance of the descriptors. In this study, the electrophilic and nucleophilic interactions of diarylpyrazole-benzenesulfonamide derivatives active on human carbonic anhydrase in 3D space were analyzed using different types of Local Reactivity Descriptors (LRDs). Three different classes of descriptors used in the Molecular Conformer Electron Topology (MCET) method: (1) Atomic charge, (2) Frontier Molecular Orbital (FMO) and (3) Fukui and Klopman indices. To assess the effect of changing LRD types on the ligand side, the variations in dimensions and values of the parameters on the receptor side were calculated for 3D quantitative structure-activity relationship (3D-QSAR) models. Each model was evaluated using the Leave One Out-Cross Validation (LOO-CV) method on the training set from the split molecule series and then validated on the external test set. As a result of comparing the different LRD types, a model with satisfactory values of Q2 = 0.933 and R2 = 0.964 was selected, which consisted of the electrostatic charge and LUMO coefficient under the Klopman Index (K_I) class. The activity changes at the interaction points between the ligand and receptor (L-R) were plotted to show the Auxiliary Group (AG) and Anti Pharmacophore Shielding (APS) groups. In addition to ligand-based drug design, the binding interactions between the ligand and the identified targets were investigated through molecular docking, one of the most widely used methods in structure-based drug design.

Anil, Derya Aktas; Polat, M. Fatih; Saglamtas, Ruya; Tarikogullari, Ayse H.; Alagoz, M. Abdullah; Gulcin, Ilhami; Algul, Oztekin; Burmaoglu, Serdar

Enzyme inhibition is a very active area of research in drug design and development. Chalcone derivatives have a broad enzyme inhibitory activity and function as potential molecules in the development of new drugs. In this study, the synthesized novel halogenated chalcones with bromobenzyl and methoxyphenyl moieties were evaluated toward the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes and human erythrocyte carbonic anhydrase I (hCA I), and II (hCA II) isoenzymes. They showed highly potent inhibition ability toward AChE with Ki values of 1.83 ± 0.21–11.19 ± 0.96 nM and BChE with Ki values of 3.35 ± 0.91–26.70 ± 4.26 nM; hCA I with Ki values of 29.41 ± 3.14–57.63 ± 4.95 nM, and hCA II with Ki values of 24.00 ± 5.39–54.74 ± 1.65 nM. Among the tested enzyme inhibitions, compounds 14 and 13 were the most active compounds against AChE and BChE. Docking studies were performed to the most active compounds against AChE, BChE, hCA I and hCA II to propose a binding mode in the active site and molecular dynamics simulations were studied to check the molecular interactions and the stability of the ligands in the active site. The results may contribute to the development of new drugs particularly to treat some global disorders including Alzheimer's disease (AD), glaucoma, and diabetes.