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    Bovine carbonic anhydrase (bCA) inhibitors: Synthesis, molecular docking and theoretical studies of bisoxadiazole-substituted sulfonamide derivatives
    (Elsevier, 2024) Eybek, Abdulbaki; Kaya, Mustafa Oguzhan; Gulec, Ozcan; Demirci, Tuna; Musatat, Ahmad Badreddin; Ozdemir, Oguzhan; Oner, Mine Nazan Kerimak
    This paper describes the in vitro inhibition potential of bisoxadiazole-substituted sulfonamide derivatives (6a-t) against bovine carbonic anhydrase (bCA) after they were designed through computational analyses and evaluated the predicted interaction via molecular docking. First, in silico ADMET predictions and physicochemical property analysis of the compounds provided insights into solubility and permeability, then density functional theory (DFT) calculations were performed to analyse their ionization energies, nucleophilicity, in vitro electron affinity, dipole moments and molecular interactions under vacuum and dimethyl sulfoxide (DMSO) conditions. After calculating the theoretical inhibition constants, IC50 values determined from enzymatic inhibition were found between 12.93 and 45.77 mu M. Molecular docking evaluation revealed favorable hydrogen bonding and pi-interactions of the compounds within the bCA active site. The experimentally most active compound, 6p, exhibited the strongest inhibitory activity with a theoretical inhibition constant value of 9.41 nM and H-bonds with Gln91, Thr198, and Trp4 residues and His63 Pi-cation interactions with His63 residues. Overall, the study reveals promising bCA blocking potential for the synthesized derivatives, similar to acetazolamide.
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    Density Functional Theory, Molecular-Docking Studies and Inhibition Effects of Pharmaceutical Active Ingredients on Xanthine Oxidase
    (Springer, 2025) Kaya, Mustafa Oguzhan; Dandan, Enes; Demirci, Tuna; Ozdemir, Oguzhan; Kaya, Yesim; Arslan, Mustafa
    Xanthine oxidase (XO) is a crucial part of human metabolism because of its activity on purine metabolism. In this study, drospirenone, dutasteride, ketoprofen, miconazole, mirabegron, mycophenolate mofetil, nimesulide, phenylephrine hydrochloride, prasugrel hydrochloride, ranolazine, tropicamide, and melatonin were used as drug active ingredients and the inhibitory effect of 12 drug active ingredients on XO was evaluated in vitro at the concentration of each compound required to inhibit it by 50% (IC50). As a result of the study, dutasteride exhibited the lowest highest occupied molecular orbital-lowest unoccupied molecular orbital (triangle E = 2.522 eV) energy gap, the best isotropic polarizability (331.020 atomic units), the best docking score (-11.30 kcal/mol), and the best inhibition value (IC50 = 65.80 mu M).
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    In silico investigation of tetrazole and oxadiazole compounds as inhibitors of the dengue virus NS5 protein: Synthesis, DFT, ADME and molecular docking analysis
    (Elsevier Ireland Ltd, 2025) Demirci, Tuna; Musatat, Ahmad Badreddin; Kaya, Mustafa Oguzhan; Arslan, Mustafa
    This study investigates the therapeutic potential of novel tetrazole and oxadiazole derivatives targeting the Dengue virus NS5 protein through an integrated computational and experimental approach. A series of nitrilesubstituted 1,4-dihydropyridine (1,4DHPs) derivatives were synthesized and converted into tetrazole and 1,3,4-oxadiazole analogs using established protocols. Structural characterization was performed via NMR, FT-IR, and elemental analysis. Molecular docking studies against the NS5 protein (PDB ID: 6KR2) revealed superior binding affinities for several compounds (Delta G = -7.18 to -9.58 kcal/mol), with compound 5 exhibiting the strongest interaction (Delta G = -9.58 kcal/mol, theoretical IC50 = 94.64 nM), outperforming the reference ligand SAH (Delta G = -7.18 kcal/mol). ADME profiling demonstrated favorable drug-likeness, acceptable solubility, bloodbrain barrier penetration, and CYP450 metabolic stability. DFT analyses elucidated electronic properties, including HOMO-LUMO gaps (2.72-4.80 eV) and electrophilicity indices (13.5-23.6 eV), correlating with observed bioactivity. Toxicity predictions identified compound-specific liabilities requiring optimization. These findings highlight the promise of tetrazole-oxadiazole hybrids as potent NS5 inhibitors, warranting further preclinical validation for Dengue therapeutic development.
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    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, Mustafa
    Pyruvate 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.
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    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, Mustafa
    Polyphenol 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.
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    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, Mustafa
    In 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.
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    Synthesis, inhibition effects, molecular docking and theoretical studies as Paraoxonase 1 (PON1) inhibitors of novel 1,4-dihydropyridine substituted sulfonamide derivatives
    (Springer Birkhauser, 2023) Kaya, Mustafa Oguzhan; Demirci, Tuna; Özdemir, Oğuzhan; Çalışır, Ümit; Sönmez, Fatih; Arslan, Mustafa
    The novel sulfonamide substitute 1,4-dihydropyridine derivatives were synthesized by the method of Hantzsch reaction. They have been characterized by FT-IR spectroscopy, H-1-NMR, C-13-NMR, and elemental analysis. PON1 which is an antioxidant enzyme has important functions in cardiovascular systems. The enzyme has been purified using a two-step method such as ammonium sulfate precipitation and sepharose-4B-l-tyrosine-9-aminophenanthrene hydrophobic interaction chromatography. The results demonstrated that all the synthesized compounds inhibited PON1 enzyme. The best inhibition effect was observed in compound (1) for PON1 enzyme (IC50: 8.04 mu M, K-i: 5.43 mu M). The free radical scavenging for PON1 was discovered as 20.16 mg/mL, while drug score value was reported as 0.13 for compound (1). Furthermore, the lowest binding energy (-1.31 kcal/mol) determined by molecular docking for PON1 enzyme and the lowest LUMO-HOMO gap ( increment E = 3.12 eV) were calculated for compound (1).