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Background and purpose: Ghrelin is known as a hunger hormone and plays a pivotal role in appetite, food intake, energy balance, glucose metabolism, and insulin secretion, making it a potential target for the treatment of obesity and type 2 diabetes. The essential maturation step of ghrelin to activate the GHS-R1a is the octanoylation of the Ser3, which is catalyzed by the ghrelin O-acyltransferase enzyme (GOAT) enzyme. Therefore, the inhibition of GOAT may be useful for treating ghrelin-related diseases. Experimental approach: To discover the novel inhibitors against GOAT enzyme by a fast and accurate computational method, here, we tried to develop the homology model of GOAT. Subsequently, the generated model was stabilized by molecular dynamics simulation. The consecutive process of docking, pharmacophore mapping, and large-scale virtual screening were performed to find the potential hit compounds. Findings / Results: The homology model of the GOAT enzyme was generated and the quality of 3D structures was increased to the highest level of > 99.8% of residue in allowed regions. The model was inserted into the lipid bilayer and was stabilized by molecular dynamics simulation in 200 ns. The sequential process of pharmacophore-based virtual screening led to the introduction of three compounds including ethaverine, kaempferitrin, and reglitazar as optimal candidates for GOAT inhibition. Conclusion and implications: The results of this study may provide a starting point for further investigation for drug design in the case of GOAT inhibitors and help pave the way for clinical targeting of obesity and type 2 diabetes.

Background and purpose: Although pain is one of the most common symptoms of diseases, it is often mismanaged due to limited access to painkillers and ineffectiveness, unacceptable side effects, or the possibility of abuse. However, an alternative approach to existing analgesics is to indirectly increase endogenous pain relief pathways by neprilysin (an enkephalinase) inhibitors. This enzyme breaks down and inactivates enkephalin, dynorphin, endorphins, and their derivatives. Experimental approach: In this project, a new series of racecadotril-tetrazole-amino acid derivatives 15a-l was synthesized and characterized on the basis of IR, 1H and 13C NMR, mass spectrometry, and elemental analysis. The antinociceptive activity of synthesized compounds was assessed by a hot plate, tail-flick, and formalin assays in mice. Docking was used to identify the possible interactions between neprilysin and synthesized compounds. Findings/Results: Most of the synthesized compounds showed moderate to good analgesic effects in hot plat and tail-flick test in comparison to morphine and racecadotril. Compounds 15l and 15j were the most potent compounds. The synergistic analgesic effect of compounds 15l and 15j with morphine and the antagonistic effect of naloxone on the activity of these compounds confirm that the analgesic effect of compounds 15l and 15j could be mediated through the opioidergic system. The negative and high binding energy of docking simulation of the most potent compounds in the catalytic site of neprilysin was also in good agreement with the inhibitory activity of test compounds. Conclusion and implications: Racecadotril-tetrazole-amino acid derivatives, as potential antinociceptive agents, demonstrated moderate to good antinociceptive activities comparable with morphine and higher than racecadotril.

Background and purpose: Aberrant signaling by oncogenic RAS proteins occurs in almost all human tumors. One of the promising strategies to overcome such cancers is the inhibition of KRAS protein, a subtype of RAS family involved in cell growth, differentiation, and apoptosis, through preventing its effector, SOS1, from being attached to the protein. Experimntal approach: Herein, a virtual screening process was performed using pharmacophore search, molecular docking, and molecular dynamic simulations. A pharmacophore model was created to indicate essential features for a KRAS inhibitor and used for screening the National Cancer Institution (NCI) database to retrieve similar compounds to the pharmacophore model with more than 70% similarity. Chosen compounds were then docked into KRAS and four compounds were selected based on the highest binding scores. Next, a similarity search was done in the whole PubChem database to increase the number of potential inhibitors. The filtered compounds were docked again into KRAS and three of them were selected for molecular dynamic simulation. Findings / Results: Compounds 1a, 2d, and 3a can inhibit SOS-iKRASG12D interaction due to the higher number of interactions with the protein. Moreover, they achieved the equilibrium faster than the approved inhibitor. Conclusion and implications: Auriculasin, a polyphenol flavonoid, can be considered as a potential inhibitor of SOS1-KRAS interaction. This compound seems to be a stronger anticancer than 9LI, a known inhibitor of KRAS, due to its better docking scores. Moreover, this compound can be an appropriate candidate to be formulated as an oral drug.

A series of N-aryl-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanamides derivatives were synthesized in two steps. Phthalic anhydride and phenylalanine are first reacted under microwave radiation to form 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid, which finally took part in an amidation reaction with different anilines. The final products were characterized by infrared, proton nuclear magnetic resonance (1H NMR) and mass spectroscopy techniques. The antiepileptic activity of the synthesized compounds at a fixed dose of 10 mg/kg was evaluated by pentylenetetrazole at 70 mg/kg induced seizure threshold method in male mice (n = 5) and compared with aqueous DMSO (10 %, v/v; as negative control) and thalidomide (70 mg/kg; as positive control). The results indicated that compounds 5c, 5e, and 5f as well as thalidomide significantly have higher latency time than what observed with aqueous DMSO (P < 0.05). The seizure latency threshold for 5e and 5f were statistically similar to the results of thalidomide but compound 5c showed significantly higher latency time than thalidomide. While, the electron-deficient benzene ring (5a and 5b) has demonstrated the lowest activity but compound 5e, which is the most electron rich product among tested compounds, showed good antiepileptic activity. Molecular docking was performed in order to understand how the synthetized compounds, interact with gamma-aminobutyric acid (GABA)A receptor. Docking results were in good harmony with experimental data and indicated that lowest binding energy belongs to compound 5c, which has strongest interactions with the active site of GABAA receptor. Compound 5c could be used for further investigation.

In the current study, a series of 3,4-dihydro-2-pyridone derivatives were synthesized in a one-pot four- component reaction of Meldrum's acid, benzaldehyde derivatives, methyl acetoacetate, and ammonium acetate. SiO2-Pr-SO3H was used as an efficient catalyst for the synthesis of the target compounds under solvent-free conditions. The most probable mechanism for this reaction has been discussed. The advantages of this methodology are high product yields, being environmentally benign, short reaction times, and easy handling. Eight 2-pyridinone derivatives were evaluated for their inhibitory activities against Jack bean urease. Molecular docking study of the synthesized compounds was also evaluated. All compounds showed good activities against urease and among them, 4-(4-nitrophenyl)-5-methoxycarbonyl-6-methyl-3,4- dihydropyridone (5a) showed the most potent activity (IC50 = 29.12 µM), more potent than hydroxyurea as the reference drug (IC50 = 100.0 µM). Also, the results from docking studies were in good agreement with those obtained with in vitro assay. According to the docking studies methionine (Met) 637 and nitro phenyl ring cause n-π interaction between lone pair of sulfur atom and π aromatic ring. Moreover, hydrophobic interactions existed between compound 5a and alanine (ALA) 636, ALA 440, and isoleucine 411. The results indicated that the inhibitory activities increased with the increase of electron withdrawing ability of the groups despite a less important role of lipophilicity in increasing the inhibitory activity.

In order to evaluate the long-term viability, the iron content stability, and the labeling efficiency of mammalian cells using magnetic cell labeling; dextran-coated ultrasmall superparamagnetic iron oxide (USPIOs) nanoparticles with plain surfaces having a hydrodynamic size of 25 nm were used for this study. Tests were carried out in four groups each containing 5 flasks of 5.5 × 10 6 AD-293 embryonic kidney cells. The cell lines were incubated for 24 h using four different iron concentrations with and without protamine sulfate (Pro), washed with phosphate-buffered saline (PBS) and centrifuged three times to remove the unbounded USPIOs. Cell viability was also verified using USPIOs. There were no significant differences in the cell viability between the control group of cells and those groups with iron uptake at the specified iron concentrations. The average iron uptake ratio compared to that of the control group was (114 ± 1). The magnetic resonance images (MRI) at post-labeling day 1 and day 21 showed (75 ± 4)% and (22 ± 5)% signal decrements compared to that of the control, respectively. The Perl′s Prussian blue test showed that 98% of the cells were labeled, and the iron concentration within the media did not affect the cell iron uptake. Magnetic cellular labeling with the USPIO-Pro complex had no short or medium term (3 weeks) toxic effects on AD-293 embryonic kidney cells.

Background: Endometriosis is a multifactorial hormonally related complex disease with unknown etiology. Epidemiologic data were suggested the possible effects of endocrine disrupting chemicals such as bisphenol A (BPA) on endometriosis. BPA is similar to endogenous estrogen and has the ability to interact with estrogen receptors and stimulate estrogen production. Our aim was to evaluate the relationship between urinary BPA concentrations in women with endometrioma. Materials and Methods: This case–control study consisted of fifty women who have been referred to gynecology and infertility center with endometrioma and were candidates for operative laparoscopy and ovarian cystectomy as cases. Fifty women who had not any evidence of endometrioma in clinical and ultrasound evaluation and came to the same clinic for routine check-up were selected as controls. One-time urine sample was collected after receiving informed consent before surgery and medical intervention. Total BPA in urine was measured with high-performance liquid chromatography method and detection limit was 0.33 ng/mL. Results: Percentage of urine samples containing BPA was 86% of cases and 82.4% of control. Urinary BPA showed a right-skewed distribution. The mean concentration of BPA was 5.53 ± 3.47 ng/mL and 1.43 ± 1.57 ng/mL in endometriosis and control group, respectively (P < 0.0001, Mann–Whitney U-test). The logistic regression showed that the odds ratio of the BPA was 1.74 (95% confidence interval: 1.40–2.16) after adjustment of age, parity, body mass index