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Öğe Novel Tetrazole And 1,3,4-Oxadiazole Derivatives Synthesis, Molecular Docking, Adme, Potential Activator For Rabbit Muscle Pyruvate Kinase(Univ Babes-Bolyai, 2024) Kaya, Mustafa Oguzhan; Demirci, Tuna; Karipcin, Selman; Ozdemir, Oguzhan; Kaya, Yesim; Arslan, Mustafa. The activation of muscle pyruvate kinase (PK) increases the conversion of phosphoenolpyruvate (PEP) to pyruvate, which results in the production of ATP. This is critical for supplying the energy needed for muscle contraction. In this study, we synthesized 1,4-dihydropyridine/pyridine compounds bearing tetrazole and 1,3,4-oxadiazole groups by using Hantzsch method and characterized by FT-IR spectroscopy, elemental analysis, and The studies revealed that all original synthesized compounds activated PK and AC50 (half-maximal activating concentration) values of the compounds were extremely effective (1.30 mu M to 14.65 mu M).Öğe Rabbit muscle pyruvate kinase activators: Synthesis, molecular docking and theoretical studies of N-substituted sulfonamide derivatives(Elsevier, 2024) Kaya, Mustafa Oguzhan; Demirci, Tuna; Musatat, Ahmad Badreddin; Ozdemir, Oguzhan; Sonmez, Fatih; Kaya, Yesim; Arslan, MustafaPyruvate kinase (PK) activators have potential therapeutic applications in diseases such as sickle cell anemia. In this study, N-Substituted sulfonamide derivatives of 1,4-dihydropyridines were synthesized and evaluated as PK activators in vitro and using molecular docking studies. The compounds were synthesized by reacting dicarbonyl compounds with ammonium acetate, 5-nitrobenzaldehyde, and alumina sulfuric acid (ASA), followed by reduction and sulfonylation. The structures of the compounds were analyzed using spectroscopic techniques. DFT calculations provided insights into the electronic properties. Molecular docking of the compounds into the active site of PK showed favorable binding interactions. ADME evaluation indicated suitable solubility, BBB permeation, and lack of CYP450 inhibition. Overall, this study demonstrates the potential of new hybrid 1,4-dihydropyridine substituted sulfonamides as PK activators for further development. According to AC50 values, the compound (DTS-F-7, 0.97 mu M) is about 100-fold higher affective than the clinically used sulfonamide compound (AC50 = 90 mu M) for PK.Öğe Rational Design, Synthesis, and Computational Investigation of Dihydropyridine [2,3-d] Pyrimidines as Polyphenol Oxidase Inhibitors with Improved Potency(Springer, 2024) Kaya, Mustafa Oguzhan; Kerimak-Oner, Mine Nazan; Demirci, Tuna; Musatat, Ahmad Badreddin; Ozdemir, Oguzhan; Kaya, Yesim; Arslan, MustafaPolyphenol oxidase (PPO) is an industrially important enzyme associated with browning reactions. In the present study, a set of ten new dihydropyridine [2,3-d] pyrimidines (TD-Hid-1-10) were synthesized and was found to be proven characteristically by 1H NMR, 13C NMR, IR, elemental analysis, and assessed as possible PPO inhibitors. PPO was purified from banana using three-phase partitioning, achieving an 18.65-fold purification and 136.47% activity recovery. Enzyme kinetics revealed that the compounds TD-Hid-6 and TD-Hid-7 are to be the most potent inhibitors, exhibiting mixed-type inhibition profile with IC50 values of 1.14 mu M, 5.29 mu M respectively against purified PPO enzyme. Electronic structure calculations at the B3LYP/PBE0 level of theories using def-2 SVP, def2-TZVP basis sets with various molecular descriptors characterized the electronic behavior of studied derivatives TD-Hid-1-10. Molecular electrostatic potential (MEP) and reduced density gradient analyses of RDG-NCI provided insights into charge distributions and weak intermolecular interactions. Docking study simulations predicted binding poses within crucial amino acid sequence in the 2y9x enzyme's active site, which is typically similar in sequence to the PPO form is not allowed. Ligands were analysed in terms of binding energies, inhibitor concentrations (mM) and various molecular interactions such as H-bonds, H-carbon, pi-carbon, pi-sigma, pi-sigma, pi-pi T-shaped, pi-pi stacked, pi-alkyl, Van der Waals and Cu interactions. The lowest binding energy (-7.83 kcal/mol) and the highest inhibitory effect (1.83 mM) were shown by the ligand Td-Hid-6, which forms H-bonds with Met280 and Asn260, exhibits pi-sigma interactions with His61 and pi-alkyl interactions with Val283. Other ligands also showed different interactions with various amino acids; for example, the Td-Hid-1 ligand formed H-bonds with His244 and showed pi-sigma interactions with His244 and Val283.Öğe Synthesis, activatory effects, molecular docking and ADME studies as rabbit muscle pyruvate kinase activators of ureido phenyl substituted 1,4-dihydropyridine derivatives(Springer, 2024) Kaya, Mustafa Oguzhan; Demirci, Tuna; Calisir, Umit; Ozdemir, Oguzhan; Kaya, Yesim; Arslan, MustafaIn this study, the activation of pyruvate kinase enzyme in vitro via different urea substituents in the para position as functional groups of 1,4-dihydropyridine derivatives synthesized by Hantzsch reaction method was investigated. Elemental analysis, 1H-NMR, 13C-NMR and FT-IR spectroscopy were used to identify the ureido phenyl substituted 1,4-dihydropyridine derivatives. Virtual screening based on molecular docking supported the results of possible in vitro pyruvate kinase (PK) activators among the synthesized substances. The results showed that all compounds successfully activated PK. The strongest activator effect was shown by ethyl-4-(4-(4-(3-(3-methoxyphenyl)thioureido)phenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,7,8-hexahydroquinolin-3 (7) with an AC50 value of 87.70 mu M. In molecular docking studies, full compatibility (- 3016.93 FF), binding affinities (Delta G = - 8.58 kcal/mol), LUMO-HOMO energy gap (Delta E = 7.85 eV) in Density functional theory (DFT) studies and drug similarity score of the compounds were found to be 0.69. These results shed light on the therapeutic potential of the produced compounds to treat PK-related diseases.
