Ophthalmic drugs: in vitro paraoxonase 1 inhibition and molecular docking studies

Çalışkan, Büşra; Demir, Yeliz; Türkeş, Cüneyt

doi:10.1002/bab.2284

Cited by 25 publications

(22 citation statements)

References 81 publications

(92 reference statements)

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“…The prepared small molecules were docked into the binding sites of the target enzymes by the Ligand Docking module with Glide extra precision (XP) mode [ 90 – 92 ]. MM-GBSA relative binding free energy computations [ 93 – 95 ] of target proteins (4EY7, 6I0L, and 5NY3) with the agents were carried out using the Prime tool in the VSGB energy model and OPLS4 force field [ 96 , 97 ].…”

Section: Methodsmentioning

confidence: 99%

Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif

et al. 2022

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The acetylcholinesterase and carbonic anhydrase inhibitors (AChEIs and h CAIs) remain key therapeutic agents for many bioactivities such as anti-Alzheimer and antiobesity antiepileptic, anticancer, antiinfective, antiglaucoma, and diuretic effects. Here, it has been attempted to discover novel multi-target AChEIs and h CAIs that are highly potent, orally bioavailable, may be brain penetrant, and have higher effectiveness at lower doses than tacrine and acetazolamide. After detailed investigations both in vitro and in silico, novel N -substituted sulfonyl amide derivatives ( 6a–j ) were determined to be highly potent inhibitors for AChE and h CAs ( K I s are in the range of 23.11–52.49 nM, 18.66–59.62 nM, and 9.33–120.80 nM for AChE, h CA I, and h CA II, respectively). Moreover, according to the cytotoxic effect studies, such as the ADME-Tox, cortex neuron cells, and neuroblastoma SH-SY5Y cell line, compounds 6a , 6d , and 6h , which are the most potent representative versus the target enzymes, were identified as orally bioavailable, highly selective, and brain preferentially distributed AChEIs and h CAIs. The docking studies revealed precise binding modes between 6a , 6d , and 6h and h CA II, h CA I, and AChE, respectively. The results presented here might provide a solid basis for further investigation into more potent AChEIs and h CAIs. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10422-8.

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Section: Methodsmentioning

confidence: 99%

Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif

et al. 2022

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“…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 . The X‐ray structures of the templates 6E08 55 (Resolution: 1.90 Å; Species: Homo sapiens) and 4GWK 56 (Resolution: 1.53 Å; Species: Homo sapiens) were obtained from the Protein Data Bank (http://www.rcsb.org/), 57‐59 and the Protein Preparation Wizard tool 60‐62 was used to construct them as in prior investigations.…”

Section: Methodsmentioning

confidence: 99%

“…48,49 To prepare these compounds and reference ligands NAP + and 3PG, the LigPrep panel [50][51][52] was used with default parameters at a pH range of 7.0 ± 2.0 by Epik. 53,54 The X-ray structures of the templates 6E08 55 (Resolution: 1.90 Å; Species: Homo sapiens) and 4GWK 56 (Resolution: 1.53 Å; Species: Homo sapiens)…”

Section: In Silico Studiesmentioning

confidence: 99%

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

Yıldız

Demir

Küfrevioğlu

2022

J of Molecular Recognition

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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]

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“…First, the sediment was extracted from approximately 20 ml of fresh human serum using the ammonium sulfate precipitation process (60%-80%) employed in prior investigations and centrifuged at 12,500g for 30min before being dissolved in Na-phosphate buffer (100 mM, pH 7.0). [30][31][32] Second, dialyzed enzyme sample was placed in the anion exchanger column (DEAE Sephadex A-50, IEX).…”

Section: Biological Studiesmentioning

confidence: 99%

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

Korkmaz

Türkeş

Demir

et al. 2022

J Biochem & Molecular Tox

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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.

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Ophthalmic drugs: in vitro paraoxonase 1 inhibition and molecular docking studies

Cited by 25 publications

References 81 publications

Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif

Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif

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

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

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