Calcium Channel Blockers: The Effect of Glutathione S‐Transferase Enzyme Activity and Molecular Docking Studies

J Biochem & Molecular Tox

et al. 2022

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Paraoxonase 1 (PON1) can metabolize some compounds such as aromatic carboxylic acid and unsaturated aliphatic esters, arylesters, cyclic carbonate, plucuronide drugs, some carbamate insecticide classes, nerve gases, and lactone compounds. Methyl benzoate has recently been shown to display potent toxicity against several insect species. In the current study, we aimed to investigate the effect of the methyl benzoate compounds (1–17) on PON1 activity. Methyl benzoate compounds inhibited PON1 with KI values ranging from 25.10 ± 4.73 to 502.10 ± 64.72 μM. Compound 10 (methyl 4‐amino‐2‐bromo benzoate) showed the best inhibition (KI = 25.10 ± 4.73 μM). Furthermore, using the ADME‐Tox, Glide XP, and MM‐GBSA tools of the Schrödinger Suite 2021‐4, a complete ligand–receptor interaction prediction was performed to characterize the methyl benzoates (1–17), probable binding modalities versus the PON1.

Section: Methodsmentioning

confidence: 99%

Section: Computational Studiesmentioning

confidence: 99%

Methyl benzoate derivatives: in vitro Paraoxonase 1 inhibition and in silico studies

Korkmaz

Türkeş

J Biochem & Molecular Tox

et al. 2022

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“…All the samples were measured three times. IC 50 plots, Michaelis‐Menten plots, and Lineweaver‐Burk curves 55 were created, and K I constants and types of inhibition were identified based on the observed data as in our previous work 56,57 …”

Section: Methodsmentioning

confidence: 99%

N‐substituted phthalazine sulfonamide derivatives as non‐classical aldose reductase inhibitors

Türkeş

Arslan

J of Molecular Recognition

et al. 2022

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Aldose reductase (AR, AKR1B1; EC 1.1.1.21) is an aldo‐keto reductase that has been widely investigated as an enzyme crucially involved in the pathogenesis of several chronic complications, including nephropathy, neuropathy, retinopathy, and cataracts associated with diabetes mellitus. Although sulfonamides have been reported to possess many other biological activities, in continuation of our interest in designing and discovering potent inhibitors of AR, herein, we have evaluated the AR inhibitory potential of N‐substituted phthalazine sulfonamide derivatives 5a‐l. The biological studies revealed that all the derivatives show excellent activity against AR, with KI constants ranging from 67.73 to 495.20 nM. Among these agents, 4‐(6‐nitro‐1,4‐dioxo‐1,2,3,4‐tetrahydrophthalazine‐2‐carbonyl)benzenesulfonamide (5e) and 1,4‐dioxo‐3‐(4‐sulfamoylbenzoyl)‐1,2,3,4‐tetrahydrophthalazine‐6‐carboxylic acid (5f) showed prominent inhibitory activity with KI values of 67.73 and 148.20 nM, respectively, vs AR and were found to be more potent than epalrestat (KI = 852.50 nM), the only AR inhibitor currently used in the therapy. Moreover, molecular docking studies were also performed to rationalize binding site interactions of these sulfonamides (5a‐l) with the target enzyme AR. According to ADME‐Tox, predicts were also determined that these derivatives be ARIs displaying suitable drug‐like properties. The sulfonamides identified in this study may be used to develop lead therapeutic agents inhibiting diabetic complications.

“…Fluorophenylthioureas were sketched in the 2D‐sdf format using ChemDraw ver. 19.1 for Mac (PerkinElmer, Inc., Waltham, MA, USA) 48,49 . To prepare these compounds and reference ligands NAP + and 3PG, the LigPrep panel 50‐52 was used with default parameters at a pH range of 7.0 ± 2.0 by Epik 53,54 .…”

Section: Methodsmentioning

confidence: 99%

Screening of in vitro and in silico effect of Fluorophenylthiourea compounds on glucose 6‐phosphate dehydrogenase and 6‐phosphogluconate dehydrogenase enzymes

Yıldız

J of Molecular Recognition

Küfrevioğlu

2022

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Inhibition studies of enzymes in the pentose phosphate pathway (PPP) have recently emerged as a promising technique for pharmacological intervention in several illnesses. Glucose 6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) are the most important enzymes of the PPP. For this purpose, in the current study, we examined the effect of some fluorophenylthiourea on G6PD and 6PGD enzyme activity. These compounds exhibited moderate inhibitory activity against G6PD and 6PGD with K I values ranging from 21.60 ± 8.42 to 39.70 ± 11.26 μM, and 15.82 ± 1.54 to 29.97 ± 5.72 μM, respectively.2,6-difluorophenylthiourea displayed the most potent inhibitory effect for G6PD, and 2-fluorophenylthiourea demonstrated the most substantial inhibitory effect for 6PGD. Furthermore, the molecular docking analyses of the fluorophenylthioureas, competitive inhibitors, were performed to understand the binding interactions at the enzymes' binding site.6-phosphogluconate dehydrogenase, fluorophenylthiourea, glucose 6-phosphate dehydrogenase, molecular docking | INTRODUCTIONOne of the main intracellular reducing agents, nicotinamide adenine dinucleotide phosphate (NADPH), is mainly produced by the pentose phosphate pathway (PPP) and is crucial for the thioredoxin and glutathione systems. 1-4 PPP is the main pathway for glucose catabolism and the biosynthesis of aromatic amino acids, nucleic acids, glucose 6-phosphate dehydrogenase (G6PD), and 6-phosphogluconate dehydrogenase (6PGD) enzymes. These enzymes are the most important enzymes of the PPP play an essential role in the formation of NADPH. [5][6][7][8] On the other hand, an activated PPP affects tumor metabolism, such as angiogenesis, favoring tumor metastasis, promoting malignant transformation, protecting cells from apoptosis, and increasing tumor progression. [9][10][11][12] In recent years, overexpression of PPP enzymes in many types of cancer has been the focus of interest for researchers. The mechanism of PPP enzymes associated with cancer progression is still under investigation. The research found that 6PGD was regulated in many types of cancer, such as colon, leukemia, breast, ovarian, liver, and thyroid. [13][14][15] Thiourea structures have several biological activities, like anticancer and antibacterial activities, and especially on the central nervous system of rodents, they have a high impact. [16][17][18] The thiourea skeleton has an essential role in pharmaceutical chemistry. Studies have shown solid cytotoxic activity against cancer cells. [19][20][21] The desired inhibitory activity of these drugs against various inhibitors is crucial in the death of cancer cells. Recently, evaluation of novel derivatives of thiourea as anti-angiogenic and antitumor agents has been published. [22][23][24]