Letters in Drug Design & Discovery - Volume 21, Issue 17, 2024

WD repeat structural domain 5 (WDR5), which plays an important role in various biological functions through epigenetic regulation, is aberrantly expressed in human cancers, and is an effective target for the discovery of anticancer drugs.

In this paper, QSAR modeling analysis, including comparative molecular field (CoMFA) and comparative molecular similarity index analysis field (CoMSIA), was first performed using 41 pyrroloimidazole analogs. The results showed q2=0.667 and r2=0.981 in CoMFA and q2=0.662 and r2=0.983 in CoMSIA. Molecular docking and molecular dynamics simulations further confirmed the interaction and binding affinity of the inhibitors with key residues of the proteins, for example, PHE149, PHE133, and CYS261.

Based on QSAR and docking studies, seven new compounds with high scores and qualified ADMET performance were designed.

In this study, new ideas have been provided for exploring new WDR5 inhibitors.

The adenovirus vector has been widely studied for vaccines and gene therapies. During the production of the adenovirus vector, a high virus titer is desired to obtain enough virus. The adenovirus vector has been widely studied for the vaccinations and gene therapies, where a high virus titer is desired to obtain sufficient quantities of the virus. For an adenovirus vector-based vaccine, suppression of antigen expression during production would improve the virus titer during production.

This study aimed to construct an adenovirus vector with lacO-regulated antigen expression using the SARS-CoV-2 spike as a transgene model, which would improve the adenovirus titer during production.

The lacO expression cassette was designed and prepared as a synthetic gene in pUC57. The lacO expression cassette was then subcloned into pShuttle-CMV. The SARS-CoV-2 spike gene was then inserted into the pShuttle-CMV harboring lacO to generate pShuttle-lacO_S and pShuttle-lacO-intron_S. Recombinant pShuttle was then used to generate a recombinant adenovirus genome using Escherichia coli BJ5183 pAdeasy-1. Transfection of the PacI-linearized adenovirus genome into AD293 and HEK293 cells was used to generate adenovirus primary stock for 14 days of incubation.

Recombinant adenovirus genomes, pAdeasy-lacO_S and pAdeasy-lacO-intron_S, were successfully generated and characterized using PacI restriction and PCR. In the production of adenovirus primary stocks, the adenovirus titer produced in AD293 cells was higher than in HEK293 cells. The primary stock titer of AdV_lacO-intron-S was higher than AdV_lacO-S and AdV_S titers.

Production of adenovirus with lacO and spike gene, either with or without intron, was successful with a higher titer as compared to AdV_S titer.

Drug resistance poses a threat to global health given the disturbing rate at which microbiological illnesses are rising and the widespread use of antibiotics. While naturally occurring antibiotics reduce the likelihood of bacterial resistance, recognized drugs can develop the same properties when structurally modified. Metronidazole has been targeted to achieve this feat.

The purpose of this work is to enable the structural modification of metronidazole by means of electric current, using inexpensive, easily accessible magnesium ribbon as electrodes in order to produce a novel, effective antibiotic.

With magnesium ribbon electrodes, metronidazole is modified electrochemically, in an undivided cell system. Ultraviolet-visible (UV-Vis), Fourier Transform Infrared (FTIR), and Gas Chromatography-Mass Spectrometry (GC-MS) were used to characterize the product. Antibacterial activity was evaluated using the agar well diffusion method and Wistar rats were used for in vivo toxicity assessment.

2-Methyl-1-vinyl-1H-imidazol-5-amine showed good antibacterial activities compared to the standard nitrofurantoin and toxicity evaluations using Wistar rats revealed that the product might induce dose-dependent variations in kidney function biomarkers, with doses of 100 mg/kg and below. However, when the compound was administered orally, there was no significant effect on liver function, even at a dose of 1000 mg/kg.

These results point to the modified metronidazole's potential as a potent antibiotic with controllable toxicity, indicating that additional research into its pharmacological uses is necessary.

Novel sulfonamides containing pyrazole and 1,2,3-triazole were synthesized, and their inhibitory effects on six common pathogenic bacteria and COX-2 were investigated to screen new sulfonamides antimicrobial agents and COX-2 inhibitors with better effects.

The compounds with bacteriostatic effect were screened by using the ring of inhibition method and MTT chromogenic method, and the mechanism of bacteriostatic inhibition and description of bacteriostatic effect of the synthesized compounds were investigated with the aid of MOE molecular docking simulation and Gaussian molecular weighting calculations. The in vitro inhibitory effect of the synthesized compounds on COX-2 was studied using the phenylmethyl acetate color development method.

The results of bacterial inhibition experiments revealed that compounds 11d and 11e had better inhibition effects on pathogenic bacteria, especially on C. albicans, essentially the same as that of the positive control, FLUCZ. The compounds 4f, 7b, and 11c had the best inhibitory effect by COX-2 in vitro inhibition experiments, especially 11c, which had a better inhibitory effect than the positive control acetazolamide.

A series of derivatives obtained by introducing pyrazole and 1,2,3-triazole ring into sulfonamides have good bacteriostatic and COX-2 inhibition effects and have the potential to be developed as novel antimicrobial agents and enzyme inhibitors.

Temperature-sensitive (thermo-sensitive) formulations are a novel drug delivery dosage form that shows bio-inspired behavior in various applications. The structure and properties of a thermosensitive polymer are critical in designing an intelligent biometric polymer that contains lipopeptide biosurfactants.

In this study, thermo-sensitive hydrogels with lipopeptide biosurfactants as a potential wound dressing dosage form were formulated and examined regarding physicochemical properties.

The lipopeptide biosurfactants were isolated from the Acinetobacter junni B6 bacterial strain and loaded on a formulation of poloxamer 407^® and carboxymethyl cellulose as a gelling agent. Numerous experiments were carried out to evaluate the physicochemical properties of these formulations, such as the stability, spreadability, release profile, and kinetic.

The formulation (Poloxamer 407^® (19% w/v), carboxymethyl cellulose (2% w/v), lipopeptide biosurfactants (5 mg/mL), benzyl alcohol (1% v/v), and 0.1 mL polyethylene glycol 400) was select as the optimum formulation. The selected formulation released 26.9% of the lipopeptide biosurfactants with anomalous transport kinetics after 10 hours.

The results showed that a thermo-sensitive formulation could help achieve a sustained release of lipopeptide biosurfactants and potentially be used as a dressing formulation for wounds in future studies.

HIV-1, the primary causative agent of AIDS, remains a formidable and lethal virus globally, claiming the lives of millions over the past four decades since its discovery. Recent research has underscored the potential of HIV-1 protease as a therapeutic target, offering a promising strategy for inhibiting viral replication within the body.

In light of this, we have curated an extensive database comprising 193 derivatives of Darunavir (DRV), an HIV-1 protease inhibitor. Simultaneously, we have developed a comprehensive set of 3D-QSAR models to elucidate the structure-activity relationships of these 193 derivative inhibitors. Employing various computational simulation techniques, including Comparative Molecular Field Analysis (CoMFA), Comparative Similarity Indices Analysis (CoMSIA), and molecular docking, we have unveiled the fundamental three-dimensional structural features influencing their biological activity.

Results indicate that the optimal CoMSIA model (Q² = 0.500, R²ncv = 0.882, R²pred = 0.797) surpasses other models, demonstrating superior predictive capability. Furthermore, docking results suggest that DRV derivatives maintain stable conformations within the binding cavity due to synergistic interactions, such as hydrogen bonding and non-bonded interactions. Drawing insights from the best computational models, we have designed five DRV derivatives with significant HIV-1 protease inhibitory activity through local modification, with theoretical calculations indicating favorable pharmacokinetic properties and synthetic feasibility for the newly proposed molecules.

It is hoped that the findings and conclusions obtained herein may furnish theoretical underpinning and directional guidance for the design, optimization, and experimental synthesis of DRV derivative compounds for pharmaceutical purposes.

Rheumatoid arthritis (RA) is a self-inflammatory disease with increasing global morbidity and high disability. The Chinese herbal medicine Rhododendron molle G. Dons has been conventionally used to control RA without side effects for hundreds of years, but its effect and mechanism for anti-RA are still unclear.

The objective of this study is to study the potential effect and mechanism of R. molle against RA from the perspective of action targets and molecular pathways.

In this study, systemic network pharmacology was used to explore the potential effect and mechanisms of R. molle against RA, including drug active components collection, target prediction, PPI network construction, and GO and KEGG pathway enrichment analyses. At last, molecular docking was carried out to estimate the pharmacological effects and mechanisms.

A total of 19 drug-active compounds from R. molle and 188 potential therapeutic targets for RA were screened. According to the results of molecular docking, the interaction between 4 key active compounds (rhodojaponin III, quercetin, kaempferol, rhodojaponin VI) and 10 core target proteins (TNF, AKT1, ALB, IL-1β, TP53, EGFR, CASP3, MMP9, PTGS2, BCL2) is the closest. The results of enrichment analysis showed that the most enriched pathways were pathways related to inflammation, human T-cell leukemia virus type I infection, PI3K-Akt and IL-17.

The Chinese herbal medicine R. molle may regulate multiple pathways by interacting with multiple drug-active compounds and core targets, and cause the patient's immune system to respond accordingly, reducing the release of inflammatory factors, and relieving joint pain.

Dexamethasone (DEX), delivered through newly developed self-nanoemulsifying drug delivery systems, which is administered to rabbit eyes, has been presented. The instrumental parameters of the multiple LC-MS/MS methods in the literature are modified according to rabbit vitreous liquid and current laboratory conditions.

Quick optimization of the chromatographic and mass spectrometric parameters was done by inspecting the available literature for the analysis of DEX by LC-MS/MS from biological matrices. Chromatographic separation was achieved in the reverse mode using C18 (50x2.1 mm, 5 µm) as a stationary phase and acetonitrile and water with ammonium acetate as a mobile phase in gradient elution. Quantitation was done in multiple reaction monitoring (MRM) mode by following the transition of m/z 393 > m/z 373 in positive ion mode. The method was also validated in terms of selectivity, within-day accuracy and precision, linearity, and limit of detection (LOD). The extraction of DEX from rabbit vitreous liquid samples was carried out by protein precipitation using acetonitrile: water (70:30, v/v).

DEX and beclomethasone (IS) were successfully separated and detected under optimized experimental settings. The method was selective for DEX and linear in the range of 0.5 and 250 ng/ml. The lower limit of quantification (LLOQ) was determined to be 0.238 ng/ml. The percent relative standard deviation (RSD) and recovery (%) of the low, medium, and high calibration levels were below 10% and within the range of 111%-114%, respectively. RSD (%) and recovery (%) of the LLOQ were below 17% and 82%, respectively. The validated method was successfully applied for the determination of pharmacokinetic properties of newly formulated dexamethasone self-nanoemulsifying drug delivery systems (DEXSNEDDS) used to administer DEX intravitreally to the rabbit.

LC-MS/MS conditions for the analysis of LC-MS/MS were determined by examining relevant literature for accomplishing simple and practical optimization of the experimental parameters, followed by method validation and analysis of rabbit vitreous liqiud. As conclusion, pharmacokinetic data of DEXSNEDDS has been obtained in the most accurate, sensitive, economical and rational way possible.

Rheum khorasanicum is a medicinal plant that belongs to the Polygonaceae family. This family is well-known for its anticancer activities.

Due to the limited studies on the anticancer activity of R. khorasanicum, the present study aimed to evaluate the apoptotic effect of this medicinal plant on MDA-MB-231 cells as a model for an aggressive triple-negative breast cancer that has a lower treatment option.

R. khorasanicum root was collected in April, 2021 from Neyshabur, Iran, and its hydroalcoholic extract was prepared using the maceration method. The High-Performance Thin-Layer Chromatography (HPTLC) assay was used to determine the main ingredients of the extract. The viability and apoptosis of the cells were evaluated by WST-1 and the annexin-V/PI dual staining assay, respectively. The scratch assay was used to assess the migratory potential of cancer cells, and the Western blotting test was employed for determining the expression of Bcl-2, Bax, cleaved caspase- 3, cleaved caspase-7, and procaspase-7 proteins involved in the apoptotic pathway.

The yield of extract from R. khorasanicum root was 56.8 ± 11.1%. The HPTLC analysis indicated that emodin, gallic acid, and epigallocatechin were pharmacologically active compounds isolated from the hydroalcoholic extract of R. khorasanicum root. The extract showed a significant toxic effect on MDA-MB-231 cells up to 60 µg/mL concentration. R. khorasanicum root extracts also inhibited the migratory potential of MDA-MB-231 at concentrations ≥ 60 μg/mL. The plant root extract at concentrations of 60 and 100 μg/mL significantly increased the Bax/Bcl-2 ratio cleaved caspase-3, cleaved caspase-7/ procaspase-7 protein levels compared to the nontreated cells.

Our findings demonstrated that the hydroalcoholic extract of R. khorasanicum efficiently triggered the apoptosis of MDA-MB-231 cells as a suitable model for aggressive triple-negative breast cancer, possibly by decreasing their migratory potential and stimulating the apoptotic signaling pathway.

Oxidative stress plays a key role in the development of a wide range of diseases, including diabetes and cancer. Recent studies reported that the derivatives of triazole compounds have a potent antioxidant activity. Therefore, this study was designed to investigate the hepatoprotective effect of a novel newly synthesized 5-mercapto-1,2,4-triazole based on nalidixic acid [1-ethyl-3-(5-mercapto-4-(p-tolyl)-4H-1,2,4-triazol-3-yl)-7-methyl-1,8-naphthyridin] (MTTN) 3 compound against CCl4 induced oxidative stress in mice.

The MTTN compound was synthesized through the interaction and then cyclization of p-tolylisothiocyanate with nalidixic acid hydrazide. By using ¹H-NMR, ¹³C-NMR, IR, and elemental analyses, the structure of the newly synthesized MTTN compound was identified. To investigate the hepatoprotective effect of this compound, forty BALB/c mice were divided into four groups (n=10) as follows: the control group, the oxidative stress-induced group, which was intraperitoneally injected with 10% CCl4 (2 mL/kg), one pre-treatment group, which was treated orally with 200 mg/kg of MTTN compound for 8 days before being treated with CCl4 at day 8, and one post-treatment group, which was treated orally with 200 mg/kg of MTTN compound for 8 days simultaneously with CCl4 co-administration at days 3 and 5. At day 9, animals were scarified and serum and liver samples were collected.

CCl4 administration caused significant hepatotoxicity as evidenced by marked elevation in the serum activity of the liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and high blood cholesterol levels. Furthermore, the hepatic malondialdehyde (MDA) level, a marker of lipid peroxidation, was increased with CCl4 administration that was associated with a decrease in the hepatic superoxide dismutase (SOD) and catalase (CAT) activities (p < 0.05). However, pre and post-treatment with the newly synthesized MTTN compound significantly reduced the serum levels of AST, ALT, and cholesterol and reduced hepatic oxidative stress as indicated by the decrease in the hepatic MDA level and the increases in the SOD and CAT activities (p < 0.05).

This study suggests that the newly synthesized MTTN compound has a potent antioxidant property and can protect against CCl4-induced liver injury. Thus, with more clinical studies, this compound may be used as effective therapeutic agents against oxidative stress related diseases.

This study aimed to assess the combinational antidiabetic effect of catechin and metformin in streptozotocin (STZ)-induced diabetic rats.

Wistar rats were chosen and divided into five groups (n=6). STZ at the dose of 55 mg/kg was used intraperitoneally for the induction of diabetes. The combination of catechin (CTN) and metformin (MET) was administered to diabetic rats. The changes in fasting blood sugar, body weight, Hb, HbA1c, creatinine, lipid profiles (TC, HDL, LDL, and TG), biochemical parameters (SGOT, SGPT, and ALP), and endogenous antioxidant parameters (SOD, GSH, and catalase) were assessed. Histopathological study of the β-cells in islets of the pancreas, kidney tubules, and liver cells was conducted in all groups.

The result showed a significant reduction (p < 0.001) in blood sugar in the CTN and MET-treated group compared to the control group. The combination of CTN (50 mg/kg) and MET (22.5 mg/kg) significantly restored the creatinine levels and urine volumes, SGOT, SGPT, and ALP, compared to a single administration dose. The abnormal lipid profile levels (TC, LDL, TG, and HDL) and antioxidant enzymes (SOD, GSH, catalase) in diabetic control rats were restored to average levels in a significant manner. Histopathological results revealed significant alterations, including hypertrophy of islets and mild degeneration, renal necrosis, and inflammation of hepatocytes.

The findings indicate that a combination of therapy (CTN+MET) improved the protective effect of the pancreas, kidney, and liver, suggesting that the combination shows a potential anti-diabetic effect.

Inflammation is an immunological reaction against an aggressor agent. NLRP3 inflammasome is a component of the immune system, which, when excessively activated, results in several inflammatory diseases, making it an attractive target for discovering anti-inflammatory drugs. Computer-Aided Drug Design (CADD) techniques are powerful tools used to search for new drugs in less time and financial cost. Recently, studies demonstrated the CADD methods to discover information about NLRP3 inhibitors MCC950 and NP3-146. In addition, the discovery of GDC-2394 and its evaluation in clinical trials instigate new studies to find binding modes and structural attributes that can used in drug design works against this target.

Here, molecular modeling methods were used to discover the significant interactions of GDC-2394, MCC950, and NP3-146 with NLRP3 to obtain helpful information in drug design compared to other inhibitors.

Molecular docking was performed using GOLD software. The best complexes were submitted into molecular dynamics simulations using GROMACS software, and the MM-PBSA was used to provide the free binding energy, which was performed using the tool g_mmpbsa compiled in GROMACS.

The RMSD, RMSF, Rg, SASA, and H-bond plots showed that the compound was stable during MD simulation time (100 ns) for GDC-2394. The PCA analysis for all compounds verified similar variance of the complex with the inhibitors to the apo-NLRP3, indicative of stability. DCCM analysis showed the best correlation in residues 134 - 371 region, which contains critical amino acids from the binding site (Ala²²⁷, Ala²²⁸, and Arg⁵⁷⁸), besides the newly identified residues. Using MM-PBSA to provide the binding free energy, it was observed that the high affinity of the drugs against NLRP3 is related to the lower rigidity of the structure. Furthermore, we identified the critical residues Phe⁵⁷⁵, Pro³⁵², Tyr⁶³², and Met⁶⁶¹ related to the coupling process.

Thus, these discoveries may contribute to the development of new anti-inflammatory drugs, such as NLRP3 inhibitors.

Lead-like drugs, which present molecular weight (MW) < 300 Da, occupy an important space in the pharmaceutical area. Most of these small molecules have ring systems, which are important for their physicochemical properties and biological activity. Previous studies have evaluated ring systems in historic drugs or drug candidates in clinical trials.

The purpose of this work was to analyze ring systems, focusing on this group of drugs with MW < 300 Da, to obtain specific insights.

The lead-like drugs (n = 219) were obtained from previous publications and the new FDA drug approvals were obtained after that and analyzed using the DataWarrior software.

Most of the lead-like drugs (> 92%) present one or two rings, with the benzene ring and heterocycle ring systems being predominant. Pyridine, imidazole, piperidine, 4,5-dihydro-1H-imidazole, and indole are the most frequent heterocycles in this set. The higher frequency of the 4,5-dihydro-1H-imidazole ring in the lead-like drugs is worth noting, as it is not observed in other drugs. The introduction of new rings has been similar in the lead-like drugs and the historic drugs, over the years; an example would be the 1,2,4-thiadiazinane 1,1-dioxide, which is present in the antimicrobial Taurolidine, a lead-like drug, and engages in the metabolic activation of the drug.

In general, the ring systems in the lead-like drugs appear to follow similar patterns to the historic drugs. Additionally, few new ring systems are being introduced, which suggests that this is an emergent field to be explored in drug discovery.

Optimal glycemic control is crucial in type 2 diabetes treatment, with α-glucosidase inhibitors emerging as promising candidates. Avenanthramides, compounds found in oats, exhibit therapeutic potential, but their efficacy as α-glucosidase inhibitors requires thorough evaluation.

This study investigates the potential of avenanthramides and their derivatives as inhibitors of α-glucosidase for the treatment of type 2 diabetes through comprehensive computational analysis.

Structure-Based Virtual Screening of 3543 avenanthramides and their analog compounds was conducted using FlexX. The top 30 ranked compounds were subjected to visual inspection of their binding mode within the α-glucosidase binding site to eliminate false positives. The top-ranked molecule was subjected to dynamic simulation and ADMET prediction.

The results revealed that 1634 compounds were found to exhibit a greater α-glucosidase inhibitory potency than miglitol, the reference molecule. Compound S1 exhibited superior α-glucosidase inhibitory potency with a binding energy of -45.7786 kJ/mol compared to miglitol, which had a binding energy of -26.5186 kJ/mol. S1 was predicted to occupy the entire binding site with an optimized number of hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations demonstrated that S1 had a lower average RMSD (0.15 ± 0.01 nm) compared to miglitol (0.16 ± 0.01 nm), indicating superior stability within the α-glucosidase binding site. S1 exhibited favorable drug-like properties, suggesting its potential as a lead compound for further development in type 2 diabetes treatment.

These findings highlight S1's potential for diabetes treatment and pave the way for future experimental investigations. The computational approach utilized offers valuable insights into the inhibitory potential of avenanthramides, providing a foundation for further drug development for type 2 diabetes.

Berberine is an important isoquinoline alkaloid that has various pharmacological properties. The comparison of the binding pocket similarity of berberine is regarded as the starting point for deciphering various activities.

Eight berberine protein crystals were clustered and studied by molecular dynamics (MD) simulations to investigate common features of berberine binding pockets.

Root Mean Square Deviation (RMSD) results showed that berberine was able to bind to each protein in a stable manner. Residue analysis showed that the stability of residue composition of different protein pockets varied. This is also consistent with the results of the pocket similarity analysis: PS-score curves of most proteins fluctuated to varying degrees. The binding pocket of 3BTI in homogeneous protein analysis exhibited high stability (PS-scoremean = 0.703 and PS-scoremin = 0.5664). Pocket similarity analysis between two heterologous proteins showed that most of PS-score values were in the interval of 0.3-0.35, and PS-score values of 3D6Y were relatively high when compared with the other three proteins. Pocket residue matching analysis showed that GLU145/VAL147/ILE182/TYR229/GLU253 in 3D6Y can be matched structurally to the corresponding residues in 1JUM, 2QVD, and 5Y0V, respectively, which can be considered as an important pocket feature for the berberine binding. Nevertheless, the obtained matched residues are limited to the category of pocket structural similarity.

This was the first study in which dynamic comparison of berberine binding pockets were used to discover pocket patterns. These results were of great significance for the polypharmacological study, the identification of potential off-targets, and the repurposing of berberine.

Postoperative adhesions commonly occur after abdominal surgery and can lead to significant complications. There is increasing evidence that targeting the renin-angiotensin system (RAS) can reduce inflammation and fibrosis. This study investigates the therapeutic potential of enalapril, an RAS inhibitor, in a rat model of postsurgical adhesion band formation.

A total of 12 male albino Wistar rats received intraperitoneal administration of enalapril (10 mg/kg). After 9 days, the anti-inflammatory and antifibrotic effects were evaluated using RT-PCR and ELISA, alongside hematoxylin and eosin and Masson's trichrome staining.

The statistical analysis of findings showed that enalapril significantly reduced the frequency and stability of adhesion bands. It attenuated submucosal edema by suppressing pro-inflammatory cytokines, decreasing pro-inflammatory cell infiltration, and inhibiting oxidative stress at the peritoneal surgery site. Additionally, enalapril inhibited fibrotic adhesion band formation by reducing collagen deposition and suppressing the expression of profibrotic genes in peritoneal adhesion tissues.

These findings demonstrate the therapeutic potential of enalapril in preventing postsurgical adhesion band formation by inhibiting key pathological responses of inflammation and fibrosis, supporting its use as a preventive treatment in postoperative adhesion management.

In the field of pharmaceutical chemistry, the anti-cancer activity of such compounds received great attention. For both medicinal and industrial studies. Xanthene derivatives are important class of compounds that have had many applications and this enhanced their uses in recent years. Xanthene and its derivatives are extensively used scaffolds in drug designing and the development of novel anti-cancer agents due to their large pharmaceutical applications.

The 3,3-dimethyl-2,3-dihydro-1H-xanthen-1-one was used to synthesise anti-cancer agents of fused pyran, pyridine, pyridazine, and thiophene derivatives. As the potentially privileged scaffolds, xanthene-fused bicyclic heterocycles may be used to discover new drugs with similar biological targets and improved therapeutic efficacy.

The key starting compound the 3,3-dimethyl-2,3-dihydro-1H-xanthen-1-one that was used in many heterocyclization reactions through its reactions with different reagents like aryldiazonium salts, reaction with S8 and producing fused tetracyclic compounds.

Through this work, new compounds were synthesized, characterized, and evaluated toward the six cancer cell lines, namely A549, HT-29, MKN-45, U87MG, and SMMC-7721 and H460. The inhibitions on tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR for selected compounds were studied and the results were supplied by studying the mechanism of action toward EGFR. Furthermore, the morphological changes of selected cell lines by the effect of compounds 6b and 13c were studied.

We focused our attention on the synthesis of heterocyclic compounds based on xanthene moiety. After a detailed optimization study, many of the synthesized compounds can be considered anticancer agents, enhancing further studies.

N-benzoyl-N'-naphthylthiourea (BNTU) is a thiourea-derived compound that is predicted to have anti-breast cancer activity. However, their physicochemical properties, ADMET, and receptor-specific targets for their anti-breast cancer activity have not been reported.

This study aimed to predict the physicochemical properties, ADMET, and anti-breast cancer activity of BNTU and its derivatives by in silico approach.

The physicochemical and ADMET properties were predicted using the pkCSM online program and ProTox-II online tool. While the anti-breast cancer activity was predicted using the molecular docking method through the Molegro Virtual Docker (MVD) program on the HER-2 receptor. The parameter observed in the molecular docking method was the bond energy value or rerank score (RS). Compounds with small RS values were predicted to have a great activity.

Most BNTU derivatives had lower RS values than BNTU, especially 4TBBNTU, and 4CFBNTU, although their RS values were still higher than lapatinib and TAK-285. As for the reference ligand hydroxyurea, the RS value of BNTU and its derivatives was much lower. The physicochemical and pharmacokinetic properties (ADMET) of lapatinib and TAK-285 were not better than that of BNTU and its derivatives.

Five compounds that deserve to be synthesized and tested for anti-breast cancer activity in vitro and in vivo are 4TBBNTU, 3CFBNTU, 4CFBNTU, 4OCBNTU, and the lead compound BNTU.

It has been reported that PKCθ plays an important role in the immune response by regulating the cellular activity of T cells and, thus, the production of immune factors such as IL-2.PKCθ protein is mainly expressed in T lymphocytes but not much in other cells and has a very good specificity. Therefore, it is very meaningful to use PKCθ protein as a novel target for immunosuppression. PKCθ is a valuable target that can be used to develop meaningful novel selective immunosuppressive agents.

In this study, we constructed a 3-characteristic pharmacophore(RHA)and used it to perform a virtual screening of the database. Then, we performed a molecular docking analysis of the compounds that scored high. The top five compounds with molecular docking scores were used as lead compounds, and structure-based ligand design via fragment substitution was applied to them, resulting in 20077 new compounds. We performed molecular docking analysis, binding free energy calculations, molecular dynamics simulation, and ADMET prediction on these new compounds and finally identified two compounds as new PKCθ inhibitors.

Through the screening of pharmacophore, molecular design based on fragment substitution, molecular docking, we finally obtained two small molecules with higher scores than the positive control, in which the molecular docking score of P01 was -53.88 kcal/mol, and the molecular docking score of P02 was -51.20 kcal/mol, and then we performed the molecular dynamics simulation, free energy of binding calculations, and the prediction of ADMET properties for the compounds. The results showed that the ligands could form more stable complexes with the proteins, the binding free energy calculations of the ligand molecules were better than the positive control, all of them had good ADMET properties, and the compounds all had good drug similarity.

Our results provided 2 new ligands that could serve as lead compounds for new PKCθ inhibitors in the future.

In recent years, in silico computational approaches have tremendously guided computational medicinal chemists and research scientists to analyze protein structures, kinetics, functions, and molecular interactions of the administered drugs.

This study aimed to identify a novel inhibitor against SARS-CoV-2 using human CD26 and modeled spike protein through suitable in silico approaches.

In this work, molecular docking and molecular dynamics simulation experiments were conducted to gain insights into the binding affinity and stability, respectively. The docked complex of CD26 with modeled spike protein showed higher binding affinity than the complex of CD26 with resolved spike protein due to the existence of strong interactions with the crucial amino acid residues of the target proteins.

The results of the molecular dynamics simulation demonstrated that CD26 with the modeled spike protein docked complex showed good stability when compared with the resolved protein.

From this computational finding, it was also suggested that the structure was stable and would rapidly guide the discovery of potential inhibitors against COVID-19.

AHR and its signaling pathways are promising therapeutic targets for psoriasis. Recent studies in traditional Chinese medicine have confirmed that Indirubin acts as an efficient ligand of AHR, inhibiting the inflammatory response. Clarifying its mechanism of action remains essential.

This study uses bioinformatics to predict Indirubin’s potential molecular mechanism in treating psoriasis and validate the results in animal models.

Indirubin and psoriasis-related targets were screened using the TCMPSP, GeneCards, and OMIM databases. Using the STRING database, a network was constructed and enriched for target protein function. Imiquimod was used to validate the core targets in a psoriasis-like mouse model.

Network pharmacology suggested that indirubin targets pathways mainly involved in cancer, inflammation, apoptosis, and other disease mechanisms, including PI3K-Akt, IL-17, and TNF pathways related to psoriasis pathogenesis. Indirubin significantly affected the severity of imiquimod-induced skin lesions in psoriasis-like mice. It also inhibited the expression of IL-6 and il-1β inflammatory factors and rescued p65 and p-p65 expressions in psoriasis-like mice.

Network pharmacology, combined with in vitro cellular experiments, tentatively confirmed that Indirubin reduces the inflammatory response in psoriasis-like mice through the AHR/NF-κB signaling pathway.

Intra-abdominal adhesions are a commonly occurring postoperative complication following abdominopelvic surgery. Peritoneal adhesion formation can lead to infertility, chronic pelvic pain, and intestinal obstruction. The anti-inflammatory and anti-oxidant activities of Ganoderma lucidum Karst (G. lucidum) and Ziziphus jujuba Mill (Z. jujuba) have been reported. Here, we have explored the therapeutic potential of Ganoderma lucidum Karst (G. lucidum) and Z. jujuba against postsurgical adhesion band formation. The NC3Rs ARRIVE guidelines were followed during experimental studies.

G. lucidum powder (800 mg/kg) and Z. jujuba powder (400 mg/kg) were administered using oral gavage to different groups of male albino Wistar rats. After ten days of treatment, macroscopic evidence for peritoneal adhesions and adhesion band score were determined. Furthermore, the anti-inflammatory and antifibrosis effects of G. lucidum and Z. jujuba were assessed using histopathology, ELISA, and real-time polymerase chain reaction methods. Also, alterations in some oxidative stress parameters were evaluated.

G. lucidum and Z. jujuba significantly decreased adhesion bands and were associated with a reduction in inflammatory cell infiltration into damaged tissues and the mRNA and protein expression of inflammatory cytokines via modulation of TNF-α, IL-6, IL-1β, and TGF-β. Moreover, both agents inhibited fibrotic adhesion band formation by decreasing collagen deposition and reducing profibrotic marker expression, Col1A1, at the peritoneum adhesion tissues. G. lucidum and Z. jujuba improved some antioxidant factors in rats’ adhesion tissues. The result of LC-MS showed that Ganoderma lucidum Karst and Ziziphus jujuba Mill consist of components with antioxidant activity, including ganoderic acid, lucidenic acid, quercetin, linoleic acid, malic acid, and benzoic acid.

The results have demonstrated the therapeutic potential of G. lucidum and Z. jujuba in reducing peritoneal adhesion through anti-inflammatory and anti-fibrotic properties, indicating their promising value as a new therapeutic approach in preventing postsurgical adhesion.

Salmonella typhimurium is a foodborne pathogen that is a major concern for global health. Flagellin (FliC) is an essential protein in Salmonella typhimurium for both motility and virulence and is a key component of flagella. Hence, focusing on FliC protein is a promising strategy for developing new anti-Salmonella agents. Colchicum luteum, a medicinal plant, shows promising antimicrobial properties. Thus, this study explores the therapeutic potential of Colchicum luteum against FliC protein using computational methods in comparison to the standard antibiotic ciprofloxacin.

Molecular docking simulation was performed to evaluate the binding affinity and interaction pattern of bioactive compounds present in Colchicum luteum and ciprofloxacin against FliC protein. This study also analysed protein stability and dynamics studies of the apoprotein, ciprofloxacin, kesselringine, and gloriosine complexes using molecular dynamic (MD) simulation. The MMGBSA method computed binding free energies.

Through docking simulations, it was found that gloriosine and kesselringine have strong binding affinity with FliC protein, similar to ciprofloxacin. MD simulation showed consistent protein-ligand complexes during the entire simulation. The MMGBSA analysis confirmed the positive interactions observed in the docking results, showing binding free energies similar to ciprofloxacin.

This study suggests that the phytocompounds of Colchicum luteum shows promising therapeutic potential as a source for creating anti-Salmonella typhimurium agents that target FliC protein. These results suggest that Colchicum luteum may have therapeutic potential against Salmonella typhimurium infections and should be further studied through in vitro and in vivo experiments.

Severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 M^pro) has been shown to be an effective target for inhibiting novel coronaviruses, which can be used as a crucial breakthrough for developing drugs to treat the coronavirus disease 2019 (COVID-19).

To design novel SARS-CoV-2 M^pro inhibitors, we conducted 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation on 64 quinazolin-4-one derivatives.

Comparative molecular field analysis (CoMFA) model (q² = 0.590, R² = 0.962), comparative molecular similarity index analysis (CoMSIA) model (q² = 0.628, R² = 0.923), and external validation indicated that the stability, reliability, and prediction performance of our constructed model were excellent. We designed 8 inhibitors with stronger antiviral activities through the three-dimensional equipotential field. Molecular docking and MD simulation probed the interactions of compounds and SARS-CoV-2 M^pro. This indicated that amino acid residues, including Met165, Met49, and Cys145, were very important in combination with the compounds. The prediction results of ADME/T and Lipinski’s rule of five indicated that the new compounds had favorable drug-like and pharmacokinetic properties.

This study provided new ideas for exploring novel SARS-CoV-2 M^pro inhibitors against COVID-19 in the future.

The synthesis of metal-based nanoparticles through conventional methods involves harsh conditions, high costs, and severe environmental threats. To overcome these issues, researchers are nowadays focusing on eco-friendly and low-cost methods for the synthesis of nanoparticles. Finally, several plant-mediated synthesis techniques have been developed, which have various advantages, such as low-cost, environmentally friendly, and easy application. The plant extract not only serves as a reducing agent but also plays a role as a stabilizing agent. The plant-mediated synthesis provides new opportunities for cost-effective, environmentally-friendly nanoparticle synthesis with high dispersity and stability. Besides, bio-generated nanoparticles derived from plant extract have promising pharmacological applications, making them potential candidates for future medicines.

The current study aimed to synthesize zirconium oxide nanoparticles using Carya illinoinensis extract and examine their physicochemical properties. Additionally, the antimicrobial efficacy of these nanoparticles was evaluated against various pathogens, exploring their potential as potent antimicrobial agents.

The synthesized nanoparticles were analyzed and characterized by various techniques like UV-Vis spectroscopy, Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), and Energy Dispersive X-ray spectroscopy (EDX). The UV-visible peak at 216 nm confirmed the formation of ZrO2 nanoparticles. The SEM images clearly showed that nanoparticles were spherical and relatively dispersed, with few agglomerations. The EDX spectra confirmed the existence of zirconium and oxygen as the basic constituents of the sample. TEM images demonstrated nanoparticles as spherical and uniformly dispersed but agglomerated with increasing precursor concentrations and decreasing nanoparticle dispersion. Fluconazole and gentamicin were used as standards in determining the antibacterial and antifungal activities of nanoparticles.

Considering the antifungal activity, a maximum zone of inhibition of 16 µg/ml was demonstrated in the case of 2 mM as compared to 4 mM and 6 mM concentrations. The Carya illinoinensis-mediated ZrO2 nanoparticles were screened against Gram-positive (S. aureus and P. aeruginosa) and Gram-negative (S. typhi and E. coli) bacterial strains. The fabricated nanoparticles exhibited promising action against all microorganisms.

In the current study, zirconium oxide nanoparticles were synthesized by using Carya illinoinensis leaves extract as a reducing agent. The antifungal and antibacterial potential of the synthesized nanoparticles were evaluated. The green synthesis method used in this study is preferable to the others as it is more affordable, environmentally benign, and widely accessible.

This study mainly made use of network pharmacology and molecular docking to analyze the therapeutic mechanism of pulmonary arterial hypertension (PAH) by the traditional medicinal food plant Lycium barbarum L. in Ningxia.

The related targets and active compounds in PAH and Lycium barbarum L. were analyzed through the Traditional Chinese Medicine Systematic Pharmacology Database and Analysis Platform (TCMSP), GeneCards databases, Online Mendelian Inheritance in Man (OMIM) databases、Cytoscape (3.7.1) software、the STRING database、the Database for Annotation Visualization and Integrated Discovery (DAVID) database. In addition, the main active compounds were molecularly docked with key targets.

The results showed that 35 active ingredients of Lycium barbarum L. were obtained. The protein-protein interaction (PPI) network includes 140 potential target proteins. Gene Ontology (GO) enrichment analysis yielded 34 entries from three parts: biological processes, cell composition, and molecular function. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis obtained 157 pathways, mainly involving Chemical carcinogenesis receptor activation, Lipid and atherosclerosis, Hepatitis B/C, Chemical carcinogenesis reactive oxygen species, as well as Signaling pathways such as HIF-1, TNF, PI3K-Akt, and MAPK. Molecular docking results showed that the affinity of the key targets to quercetin is less than -5 kcal/mol, and the affinity with betaine is less than 0.

In conclusion, it was preliminarily predicted that the active compounds of Lycium barbarum L., such as quercetin and betaine, acted on key targets such as AKT1, EGFR, MYC played an intervention role in PAH by regulating multiple signaling pathways, which provided a theoretical basis for the development and application of Lycium barbarum L. and the treatment of PAH.

Pistacia atlantica Desf., also known as Atlantic pistachio or Mt. Atlas mastic tree, has been used in traditional medicine for its anti-inflammatory properties, helping to reduce inflammation in conditions like arthritis. Additionally, the tree's resin possesses antioxidant properties that can help protect against oxidative stress.

The anti-arthritic efficacy of Pistacia atlantica oleo-gum resin extract (PAG) remains unvalidated, as its potential therapeutic benefits have not been substantiated. In the current investigation, we have substantiated the inhibitory properties of the PAG in mitigating the development of rheumatoid arthritis induced by Complete Freund's Adjuvant in rats.

Male Wistar rats weighing 160±10 g were subjected to immunization through intradermal injection of 0.1 mL of Complete Freund's Adjuvant (CFA) into the left hind metatarsal footpad. Following the induction of adjuvant arthritis, oral administration of PAG was initiated at doses of 10, 400, and 800 mg/kg once a day. Prednisolone (10 mg/kg, daily) was employed as a positive control in this study. Various parameters, including paw swelling, arthritic index, body weight loss, spleen index, thymus index, serum cytokines, inflammatory mediators, and histological alterations, as well as nitrite glutathione and catalase level, were measured. Furthermore, the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9 were evaluated.

PAG exhibited noteworthy efficacy in attenuating paw swelling and reducing the arthritic index. Moreover, it resulted in enhanced body weight loss and a consequential reduction in the thymus index. PAG (400mg/kg) significantly decreased the level of serum nitrite in the intervention group, as well as the levels of serum glutathione. On the other hand, catalase activity increased, the activity of MMP-9 decreased, and the level of MMP-2 increased compared to the intervention group. The histopathological results revealed that PAG (at doses of 400 mg/kg) had the best therapeutic effects.

In conclusion, the present study confirms the anti-arthritic activity of PAG in rats. The extract of PAG was found to prevent rheumatoid arthritis induced by Complete Freund's Adjuvant, as evidenced by the significant suppression of paw swelling and arthritic index.

Intra-abdominal adhesions are the most frequently occurring postoperative complication following abdominopelvic surgery. Peritoneal adhesion formation can lead to infertility, chronic pelvic pain, and intestinal obstruction. Several studies have shown the potential role of metformin in reducing inflammation. Here, we explored the therapeutic potency of Metformin against postsurgical adhesion band formation.

We adopted Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines for the experimental protocol. Peritoneal adhesions were examined macroscopically. Metformin (100 mg/kg) was administered intraperitoneally in male albino Wistar rats. After 9 days, macroscopic evidence and score of fibrotic bands based on scaling methods were performed and evaluated by the Nair and Leach scoring system. Moreover, the anti-inflammatory and antifibrosis effects were investigated by using hematoxylin and eosin, Masson's trichrome staining, the enzyme-linked immunosorbent assay (ELISA), and reverse transcription polymerase chain reaction (RT-PCR).

Metformin inhibited the stabilization of adhesion bands and appeared to elicit anti-inflammatory responses by attenuating submucosal edema, suppressing proinflammatory cytokines, decreasing proinflammatory cell infiltration, and inhibiting oxidative stress at the site of peritoneal surgery. We also showed that metformin prevents fibrotic adhesion band formation by reducing excessive collagen deposition and suppression of profibrotic gene expression at the peritoneum adhesion tissues via modulation of Col 1A1/A3.

These results supported the potential application of metformin in preventing postsurgical adhesion band formation by inhibiting key pathologic responses of inflammation and fibrosis in patients post-surgery.

Cancer represents the major health problem faced by the population of the world, remaining one of the main causes of death. Hence, the development of new targeted antitumor drugs with high efficacy and lower toxicity is still needed.

As a continuation of our work to discover new molecules with cytotoxic properties, two heterocyclic scaffolds, namely indolizine, and indazole, were combined in the same molecule, aiming to improve the bioactivity. This article focused on the synthesis, characterization, and biological evaluation of a series of new indazole-indolizine hybrid compounds.

The biological potential of the synthesized compounds was investigated in vitro against the human farnesyltransferase enzyme and NCI 60 tumor cell lines panel. While the farnesyltransferase inhibitory activity was modest, a very good antiproliferative action was observed for compound 4a, which, at a concentration of 10 µM, inhibited the growth of 20 types of cancer cells by more than 50% and showed cytotoxic action against the ovarian cancer cell line OVCAR-4.

A series of novel indazole-indolizine hybrids were synthesized via a [3+2] cycloaddition reaction, fully characterized and biologically evaluated for antitumor potential.

Compound 4a could be a promising starting point in the development of new antitumoral agents. Further biological investigations will be performed to identify the biological target of the compounds. Moreover, different synthetic strategies to introduce new substituents on the indolizine core will be addressed.

Despite advancements in treatment modalities, the search for new cytotoxic agents remains vital in the fight against cancer. This ongoing effort aims to introduce novel molecules that serve as potent cytotoxic agents while minimizing adverse effects.

The objective of the study is to design, synthesize, and evaluate Fmoc-L-Lysine Carboxamides for cytotoxic activities.

The title compounds 4a-l were synthesized by esterification followed by reduction of Fmoc-Lys (Boc)-OH to alcohol, then coupled with various aryl/alkyl/alicyclic carboxylic acids. These compounds were then analysed using ¹³C NMR, ¹H NMR, FT-IR, and Mass spectroscopic techniques and evaluated for cytotoxic activity by MTT assay, apoptosis induction, cell cycle analysis, EGFR-TK inhibition activity, molecular docking, and molecular dynamics simulation studies.

The results obtained by MTT assay indicated that compounds 4f and 4i demonstrated significant cytotoxicity against A549 and SKOV3 cell lines, with IC50 values of 2.75 and 1.91μM compared to doxorubicin. Further, the analysis of the Cell cycle and apoptosis proposed that 4f arrested the cell cycle in the G0/G1 phase, whereas 4i arrested the cell cycle in the G2/M phase and triggered apoptosis in cancer cells. Notably, compound 4i demonstrated the highest inhibition of EGFR with IC50, 0.189μM, and acted as its potential inhibitor. Molecular docking and dynamics simulation studies further confirmed the stability of 4i in the active site of EGFR.

Overall, these results suggested that the synthesized derivatives offer a promising approach for the advancement of new and effective cancer therapies.

The aim of this study was to explore the mechanisms of Trigonella foenum-graecum L. (T. foenum-graecum) in the treatment of type 2 diabetes mellitus (T2DM).

The TCSMP database was utilized to obtain the constituents and targets of T. foenum-graecum. The OMIM database was used at GeneCard to acquire T2DM targets. The STRING database was used to plot the PPI network. KEGG and GO analyses were performed using the DAVID database. HepG2 cells were induced to construct an insulin resistance (IR) model by a complex composed of glucose and oleic acid, and cell viability, inflammatory factors, and RAGE/PI3K/Akt signaling pathway were verified by in vitro cell experiments.

In the network pharmacology study, 14 active ingredients were screened, corresponding to 280 targets. There were 1477 targets associated with T2MD. These components may act on core targets of T2DM, such as AKT1, TNF, and IL-6, and regulate signaling pathways such as cancer pathway and AGE-RAGE to play an anti-T2DM role. In vitro results showed that quercetin and kaempferol with 5, 10, 25 μmol·L^-1 and diosgenin with 0.5, 1, 2 μmol·L^-1 could reduce the expression of TNF-α and IL-6 in IR-HepG2 cells, down-regulate the expression of RAGE, up-regulated the expression of p-PI3K/PI3K and p-Akt/Akt.

The research explored the mechanism of T. foenum-graecum anti-T2DM, which may be helpful for the development of anti-T2DM drugs for T. foenum-graecum.

Imatinib, a frontline targeted-therapeutic agent for patients with chronic myelogenous leukemia (CML), was a synthetic tyrosine kinase inhibitor approved by the US Food and Drug Administration.

To expand the structural diversity of Bcr-Abl inhibitors, we synthesized nine novel imatinib analogues (1a-1i) and evaluated their cytostatic effects against human cancer cell lines in vitro.

Imatinib and its analogues were successfully synthesized by an improved method in six main steps. Inhibitory activities of all compounds were evaluated on K562, HL-60, MCF-7, A549 and PBMC in vitro. Then, the effect of the most active compound was studied using flow cytometer, real-time qPCR and western blot experiments to determine its mechanism action. Finally, the molecular docking of the most active compound were determined.

The IC50 of one imatinib analogue (compound 1h) for K562 and HL-60 was lower than imatinib itself. Further studies indicate that the pro-apoptotic effect of compound 1h on K562 cells was stronger than imatinib over a range of concentrations. Importantly, the real-time qPCR and western blot experiments showed that compound 1h was superior to imatinib in inhibiting Bcr-Abl expression. The structure-activity relationship was analyzed by determining the inhibitory rate of each imatinib analogue. Introducing benzene (A ring) and piperidine (E ring) rings instead of pyridine (A ring) and piperazine (E ring) in imatinib significantly enhanced the potency of imatinib against K562 and HL-60 cell lines, which is consistent with the docking results.

Imatinib analogue 1h showed a better inhibitory effect on leukemia cell lines than other cell lines, which was consistent with the imatinib-like structure, moreover, had little effect on PBMC. Overall, we conclude that compound 1h has the potential to treat chronic myeloid leukemia.

Approximately 10%-40% of the global population is affected by allergic rhinitis, and Lycium barbarum has a long history of dual use as a herbal medicine and also as a food. This study utilized network pharmacology and molecular docking to explore the mechanism of action of Lycium barbarum in treating allergic rhinitis.

We screened active ingredients and potential action targets of Lycium barbarum using the TCMSP database. Relevant targets for allergic rhinitis diseases were accessed through the GeneCards and OMIM databases. GO function enrichment and KEGG pathway enrichment analyses of key targets were conducted using the DAVID database. Molecular docking validation was performed using Autodock Vina software to confirm the affinity between the core protein targets and the key active ingredients.

Network pharmacological analysis identified 35 major active ingredients of Lycium barbarum, 87 drug targets, and 2200 disease targets. GO functional analysis and KEGG pathway enrichment analysis revealed that the mechanism of action of Lycium barbarum in treating allergic rhinitis involves multiple pathways, including the HIF-1 signaling pathway, IL-17 signaling pathway, and TNF signaling pathway. Molecular docking results demonstrated good binding activity between the main active ingredients and the core protein target.

Lycium barbarum exhibits multi-component, multi-target, and multi-pathway actions in treating allergic rhinitis by regulating relevant pathways and targets.