Letters in Drug Design & Discovery - Current Issue

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.