Exploration of the photothermal role of curcumin-loaded targeted carbon nanotubes as a potential therapy for melanoma cancer.

In this research, the hydrophilic structure of multi-walled carbon nanotubes (MWCNTs) was modified by synthesizing polycitric acid (PCA) and attaching folic acid (FA) to create MWCNT-PCA-FA. This modified nanocomplex was utilized as a carrier for the lipophilic compound curcumin (Cur). Characterization techniques including TGA, TEM, and UV-visible spectrophotometry were used to analyze the nanocomplex. The mechanism of cancer cell death induced by MWCNT-PCA-FA was studied extensively using the MTT assay, colony formation analysis, cell cycle assessment via flow cytometry, and apoptosis studies. Furthermore, we assessed the antitumor efficacy of these targeted nanocomplexes following exposure to laser radiation. The results showed that the nanocomposites and free Cur had significant toxicity on melanoma cancer cells (B16F10 cells) while having minimal impact on normal cells (NHDF cells). This selectivity for cancerous cells demonstrates the potential of these compounds as therapeutic agents. Furthermore, MWCNT-PCA-FA/Cur showed superior cytotoxicity compared to free Cur alone. Colony formation studies confirmed these results. The researchers found that MWCNT-FA-PCA/Cur effectively induced programmed cell death. In photothermal analysis, MWCNT-PCA-FA/Cur combined with laser treatment achieved the highest mortality rate. These promising results suggest that this multifunctional therapeutic nanoplatform holds the potential for combination cancer therapies that utilize various established therapeutic methods.

A combination of virtual screening, molecular dynamics simulation, MM/PBSA, ADMET, and DFT calculations to identify a potential DPP4 inhibitor.

DPP4 inhibitors can control glucose homeostasis by increasing the level of GLP-1 incretins hormone due to dipeptidase mimicking. Despite the potent effects of DPP4 inhibitors, these compounds cause unwanted toxicity attributable to their effect on other enzymes. As a result, it seems essential to find novel and DPP4 selective compounds. In this study, we introduce a potent and selective DPP4 inhibitor via structure-based virtual screening, molecular docking, molecular dynamics simulation, MM/PBSA calculations, DFT analysis, and ADMET profile. The screened compounds based on similarity with FDA-approved DPP4 inhibitors were docked towards the DPP4 enzyme. The compound with the highest docking score, ZINC000003015356, was selected. For further considerations, molecular docking studies were performed on selected ligands and FDA-approved drugs for DPP8 and DPP9 enzymes. Molecular dynamics simulation was run during 200 ns and the analysis of RMSD, RMSF, Rg, PCA, and hydrogen bonding were performed. The MD outputs showed stability of the ligand-protein complex compared to available drugs in the market. The total free binding energy obtained for the proposed DPP4 inhibitor was more negative than its co-crystal ligand (N7F). ZINC000003015356 confirmed the role of the five Lipinski rule and also, have low toxicity parameter according to properties. Finally, DFT calculations indicated that this compound is sufficiently soft.

Novel 1,4 benzothiazine 3-one derivatives as anticonvulsant agents: Design, synthesis, biological evaluation and computational studies.

In this study, two series of novel 1,4-benzothiazine-3-one derivatives with alkyl substitution (series 1: 4a-4f) and aryl substitution (series 2: 4g-4l) were designed and synthesized based on the chemical scaffolds of perampanel, hydantoins, progabide and etifoxine as anti-convulsant agents. The chemical structures of the synthesized compounds were confirmed by FT-IR, 1H NMR and 13C NMR spectroscopy. Anti-convulsant effect of the compounds was examined through intraperitoneal pentylenetetrazol (i.p. PTZ) induced epilepsy mouse models. Compound 4h (4-(4-bromo-benzyl)- 4 H-benzo[b] [1,4] thiazin-3(4 H)-one) demonstrated a promising activity toward chemically-induced seizure experiment. Molecular dynamics simulation on GABA-Aergic receptors as a plausible mechanism were also done to achieve the binding and orientation of compounds in the active site of the target to evaluate the results of docking and experimental studies. The computational results were confirmed the biological activity. DFT study of 4c and 4h was performed on B3LYP/6-311 G** level of theory. Reactivity descriptors such as HOMO, LUMO, electron affinity, ionization potential, chemical potential, hardness and softness were studied in detail and show that 4h has higher activity than 4c. Also, the frequency calculations were performed on the same level of theory and the results are in line with experimental data. Moreover, in silico ADMET properties were done to establish a relationship between the physiochemical data of the designed compounds and their in-vivo activity. Appropriate plasma protein binding and high blood-brain barrier penetration are the main features of desired in-vivo performance.

Structure-based virtual screening, molecular docking, molecular dynamics simulation and MM/PBSA calculations towards identification of steroidal and non-steroidal selective glucocorticoid receptor modulators.

Glucocorticoids have been used in the treatment of many diseases including inflammatory and autoimmune diseases. Despite the wide therapeutic effects of synthetic glucocorticoids, the use of these compounds has been limited due to side effects such as osteoporosis, immunodeficiency, and hyperglycaemia. To this end, extensive studies have been performed to discover new glucocorticoid modulators with the aim of increasing affinity for the receptor and thus less side effects. In the present work, structure-based virtual screening was used for the identification of novel potent compounds with glucocorticoid effects. The molecules derived from ZINC database were screened on account of structural similarity with some glucocorticoid agonists as the template. Subsequently, molecular docking was performed on 200 selected compounds to obtain the best steroidal and non-steroidal conformations. Three compounds, namely ZINC_000002083318, ZINC_000253697499 and ZINC_000003845653, were selected with the binding energies of -11.5, -10.5, and -9.5 kcal/mol, respectively. Molecular dynamic simulations on superior structures were accomplished with the glucocorticoid receptor. Additionally, root mean square deviations, root mean square fluctuation, radius of gyration, hydrogen bonds, and binding-free energy analysis showed the binding stability of the proposed compounds compared to budesonide as an approved drug. The results demonstrated that all the compounds had suitable binding stability compared to budesonide, while ZINC_000002083318 showed a tighter binding energy compared to the other compounds.Communicated by Ramaswamy H. Sarma.

Does trigonelline help skin tone? Molecular docking studies of trigonelline on the human tyrosinase, formulation, optimization, and characterization of an emulgel-containing Trigonella foenum-graecum L. fenugreek standardized hydroalcoholic extract.

AIMS: This study aimed to perform molecular docking studies to identify possibilities of the inhibitory potential of the trigonelline present in fenugreek seeds on the human tyrosinase, standardize fenugreek extract, formulate, and characterize an emulgel-containing fenugreek extract-entrapped niosomal vesicles. MATERIALS AND METHODS: The docking study was performed using AutoDock software. The extract was standardized by the RP-HPLC method. Emulgels containing fenugreek extract and fenugreek extract-entrapped niosomes were optimized by the D-optimal method. In vitro characterization and stability studies were also carried out. RESULTS: The lowest energy docked poses of trigonelline on the human tyrosinase complex was calculated -5.8 kcal/mol. Also, in vitro assessment of the tyrosinase inhibitory effect of trigonelline and comparison of IC50 values of trigonelline and kojic acid revealed that the enzyme inhibition efficacy of trigonelline was stronger than that of kojic acid. Optimization led to emulgels with desired viscosity, droplet size, and spreadability values. The release study showed that trigonelline was released from the niosomes at a lower rate compared with extract containing emulgel. Permeation investigations revealed that trigonelline in niosomes has a higher ability to permeate through the skin. CONCLUSION: In conclusion, in silico and in vitro studies have shown that trigonelline can be assumed as an appropriate candidate for developing new cosmetic preparations and nonionic surfactant vesicles help trigonelline to permeate through the skin to a higher extent. However, clinical trials should be performed to confirm these findings.

Efficient synthesis of 1,3-naphtoxazine derivatives using reusable magnetic catalyst (GO-Fe3O4-Ti(IV)): anticonvulsant evaluation and computational studies.

A series of 2-aryl/alkyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines (S1-S11) were synthesized with an eco-friendly and recoverable nanocatalyst (GO-Fe3O4-Ti(IV)) as an efficient magnetic composite. The new nanocatalyst was characterized by FT-IR, XRD and, EDS analysis. A conformable procedure, easy to work up and having a short reaction time with high yields are some advantages of this method. The new catalyst is also thermal-stable, reusable and, environment-friendly. The chemical structures of the synthesized 1,3-oxazine compounds were confirmed by comparing their melting points with those reported in literature. Then, the anticonvulsant activity of these compounds was assessed by the intraperitoneal pentylenetetrazole test (ipPTZ). Compounds S10 and S11 displayed considerable activity against chemically-induced seizure tests. The molecular simulation was also done to achieve their binding affinities as γ-aminobutyric acid A (GABA-A) receptor agonists as an assumptive mechanism of their anticonvulsant action. The result of molecular studies represented strongly matched with biological activity. Molecular docking simulation of the potent compound (S10) and diazepam as the positive control was performed and some critical residues like Thr262, Asn265, Met286, Phe289, and Val290 were identified. Based on the anticonvulsant results and also in silico ADME predictions, S11 can be to become a potential drug candidate as an anticonvulsant agent.

Anticonvulsant activity, molecular modeling and synthesis of spirooxindole-4H-pyran derivatives using a novel reusable organocatalyst.

Fifteen derivatives of spirooxindole-4H-pyran (A1-A15) were subjected to evaluate through intravenous infusion of pentylenetetrazole (PTZ)-induced epilepsy mouse models. Four doses of the compounds (20, 40, 60 and 80 mg/kg) were tested in comparison with diazepam as positive control. The resulted revealed that compounds A3 and A12 were the most active compounds and indicated significant anticonvulsant activity in the PTZ test. The tested compounds were prepared via a multicomponent reaction using graphene oxide (GO) based on the 1-(2-aminoethyl) piperazine as a novel heterogeneous organocatalyst. The prepared catalyst (GO-A.P.) was characterized using some diverse microscopic and spectroscopic procedures as well. The results showed high catalytic activity of the catalyst in the synthesis of spirooxindole-4H-pyran derivatives. The GO-A.P. catalyst was reusable at least for 5 times with no significant decrease in its catalytic action. In silico assessment of physicochemical activity of all compounds also were done which represented appropriate properties. Finally, molecular docking study was performed to achieve their binding affinities as γ-aminobutyric acid-A (GABA-A) receptor agonists as a plausible mechanism of their anticonvulsant action. Binding free energy values of the compounds represented strongly matched with biological activity.

Atomistic insight into 2D COFs as antiviral agents against SARS-CoV-2.

The recent pandemic of COVID-19 has raised global health concerns. Preventing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) activity in the body is a very promising method to overcome the COVID-19 pandemic. One of the prevention methods is constraining the binding process among the human cell receptor-ACE2 and coronavirus spike protein. In the research done, the effect of deformation of the spike protein structure, due to the covalent organic frameworks (COFs), in reducing the interactions of ACE2 and the spike protein by the computational method was investigated. In this regard, atomic analysis of the interactions of ACE2 and the spike protein is provided using a molecular dynamics simulation. First, we investigated the interactions of the three different COFs, including COF-78, DAAQ-TFP, and COF-OEt, with the spike protein by analyzing the bond energies, as well as structural changes of the spike protein. Then, intermolecular interactions of the deformed spike protein along with ACE2 were assessed to clarify the protein's fusion after the deformation. As indicated by the results, although all introduced COFs deformed the spike protein in an effective way, COF-78 showed the best performance in the prevention of spike protein-ACE2 interactions by changing the molecular structure of the protein. Indeed, the interaction analysis of the deformed spike protein by COF-78 with the ACE2 showed that their interactions had the lowest absolute value of energy, along with the least amount of hydrogen bonds, in which the compaction of the protein was lower compared to the other deformed proteins. Moreover, having a high contact area with an aqueous media as well as severe fluctuations during the simulation time confirmed the positive performance of COF-78. In the current study, we aimed to introduce novel materials and COVID-19 prevention methodology that can be used in face masks and for surface disinfection.

De novo design of novel protease inhibitor candidates in the treatment of SARS-CoV-2 using deep learning, docking, and molecular dynamic simulations.

The main protease of SARS-CoV-2 is a critical target for the design and development of antiviral drugs. 2.5 M compounds were used in this study to train an LSTM generative network via transfer learning in order to identify the four best candidates capable of inhibiting the main proteases in SARS-CoV-2. The network was fine-tuned over ten generations, with each generation resulting in higher binding affinity scores. The binding affinities and interactions between the selected candidates and the SARS-CoV-2 main protease are predicted using a molecular docking simulation using AutoDock Vina. The compounds selected have a strong interaction with the key MET 165 and Cys145 residues. Molecular dynamics (MD) simulations were run for 150ns to validate the docking results on the top four ligands. Additionally, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and hydrogen bond analysis strongly support these findings. Furthermore, the MM-PBSA free energy calculations revealed that these chemical molecules have stable and favorable energies, resulting in a strong binding with Mpro's binding site. This study's extensive computational and statistical analyses indicate that the selected candidates may be used as potential inhibitors against the SARS-CoV-2 in-silico environment. However, additional in-vitro, in-vivo, and clinical trials are required to demonstrate their true efficacy.

Potential inhibitors of the main protease of SARS-CoV-2 and modulators of arachidonic acid pathway: Non-steroidal anti-inflammatory drugs against COVID-19.

The main protease of SARS-CoV-2 is one of the key targets to develop and design antiviral drugs. There is no general agreement on the use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19. In this study, we investigated NSAIDs as potential inhibitors for chymotrypsin-like protease (3CLpro) and the main protease of the SARS-CoV-2 to find out the best candidates, which can act as potent inhibitors against the main protease. We also predicted the effect of NSAIDs on the arachidonic pathway and evaluated the hepatotoxicity of the compounds using systems biology techniques. Molecular docking was conducted via AutoDock Vina to estimate the interactions and binding affinities between selected NSAIDs and the main protease. Molecular docking results showed the presence of 10 NSAIDs based on lower binding energy (kcal/mol) toward the 3CLpro inhibition site compared to the co-crystal native ligand Inhibitor N3 (-6.6 kcal/mol). To validate the docking results, molecular dynamic (MD) simulations on the top inhibitor, Talniflumate, were performed. To obtain differentially-expressed genes under the 27 NSAIDs perturbations, we utilized the L1000 final Z-scores from the NCBI GEO repository (GSE92742). The obtained dataset included gene expression profiling signatures for 27 NSAIDs. The hepatotoxicity of NSAIDs was studied by systems biology modeling of Disturbed Metabolic Pathways. This study highlights the new application of NSAIDs as anti-viral drugs used against COVID-19. NSAIDs may also attenuate the cytokine storm through the downregulation of inflammatory mediators in the arachidonic acid pathway.

Exploring pH dependent delivery of 5-fluorouracil from functionalized multi-walled carbon nanotubes.

Multi-walled carbon nanotubes (MWCNTs) can be applied for pH-sensitive delivery of anticancer drugs. Due to the importance of 5-fluorouracil (5-FU) in different tumor therapy regimens, it has been widely used in different pH dependent drug delivery systems. To investigate the pH effects on loading (and release) of 5-FU on (and from) the functionalized MWCNTs and propose the optimum condition for drug delivery, both macroscopic and microscopic studies were carried out using chromatography and molecular dynamic simulation at different conditions. For both levels of studies, different analytical approaches were performed to assess the validity of the methods. The experimental results revealed that 5-FU has more binding affinity to the surface of the nanocarrier at physiological pH (pH = 7.4) and showed more release at acidic conditions (pH = 5.0). Meanwhile it has been observed that basic pH (pH = 9.0) can lead to a dramatic decrease effect on loading of the drug. The results of this study can be used to suggest the optimum pH levels for nanocarbon based formulations of 5-FU in cancer therapy.

PC-ANN assisted to the determination of Vanadium (IV) ion using an optical sensor based on immobilization of Eriochorome Cyanine R on a triacetylcellulose film.

More detailed analytical studies of an optical sensor based on immobilization of Eriochorome Cyanine R (ECR) on a triacetylcellulose film have been described to determine Vanadium (IV) ions in some real samples. The sensor based on complex formation between Vanadium (IV) ions and ECR in acidic media caused the color of the film to change from violet to blue along with the appearance of a strong peak appears at 595 nm. At the optimal conditions, the calibration curve showed a linear range of 9.90×10(-7)-8.25×10(-5)mol L(-1). Vanadium (IV) ions can be detected with a detection limit of 1.03×10(-7)mol L(-1) within 15 min depending on its concentration. Also, the working range was improved by using PC-ANN algorithm. The sensor could regenerate with dilute acetic acid solution and could be completely reversible. The proposed sensor was successfully applied for determining V (IV) ions in environmental water and tea leaves.