Letters in Drug Design & Discovery - Online First

The current use of Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) inhibitors is often limited by low selectivity and adverse side effects, highlighting the urgent need for novel, highly selective agents targeting this receptor.

Based on existing VEGFR-2 inhibitors, we employed computer-aided drug design (CADD) techniques to develop a virtual compound library using active docking fragments. Molecular docking was performed using the configuration of VEGFR-2 as the receptor protein(PDB:4ASD). Comparative analysis and screening identified the most promising inhibitor, which was subsequently validated through molecular dynamics simulations.

From the virtual library, 10 potential highly active inhibitors were identified. In particular, Compound 9 demonstrated strong binding affinity with the protein configuration, forming four hydrogen bonds during docking. The calculated CODOCKER energy was 39.7315 kcal/mol, with an RMSD of 0.4634 nm and RMSF of 0.3234 nm. Compared to Sorafenib, Compound 9 exhibited superior docking selectivity and activity.

Computational analyses suggest that Compound 9 is a promising candidate as a highly selective VEGFR-2 inhibitor. Nonetheless, due to the inherent limitations of in silico docking studies, further chemical synthesis and experimental biological validation are required to confirm its potential.

Dermatophytosis is a significant global health issue that poses a serious risk to public well-being. This fungal infection occurs when dermatophytes invade the outer surfaces of both human and animal bodies. The use of common anti-dermatophyte medications has some limitations due to their side effects and drug resistance. Herbal remedies offer broad-spectrum antimicrobial effects low toxicity, and are widely used compared to traditional chemical fungicides. Recent studies have indicated that the ozone has antifungal activity due to its high oxidizing power and skin penetrating capacity.

This study examined the antifungal effects of ozonated olive oil in treating dermatophytosis caused by Trichophyton mentagrophytes through in vitro and in vivo tests on rats. The agar dilution method was used to establish the treatments' minimum inhibitory concentrations (MICs). For the in vivo study, thirty male Wistar albino rats from the Laboratory Animal Unit were prepared. The topical antifungals were then applied topically once daily for 7 days to the animals beginning 10 days after the appearance of symptoms. Five groups of animals were treated with virgin olive oil, ozonated olive oil (1.25, 2.5, or 5 mg/mL), and terbinafine (1.25 g/mL).

Following the therapy period, clinical and mycological efficacies were assessed. Ozonated olive oil and terbinafine were shown to have MIC of 2.5 µg/mL and 0.62 µg/mL against T. mentagrophytes, respectively. Ozonated olive oil showed antifungal effects and significantly reduced the clinical score by increasing hair growth and decreasing inflammation, similar to terbinafine.

Therefore, ozonated olive oil may serve as an alternative treatment for Trichophyton infections.

Synthetic antibiotics are often much more potent than natural alternatives. They can effectively treat serious and life-threatening bacterial infections.

The chalcones were synthesized by Claisen-Schmidt condensation and characterized by FT-IR, 1HNMR, 13CNMR and MS methods. All the compounds underwent computational and in-vitro evaluations for antimicrobial and antioxidant properties.

The docking studies indicated that all the molecules displayed good binding energy with their selective targets, with 6g and 6h showing the best affinity among them. The antimicrobial test results showed that the MIC values ranged from 0.4 to 0.9 mg/ml, and compounds 6g and 6h demonstrated potential for gram-positive bacteria. At the same time, 6k and 6l displayed good inhibition activity against gram-negative bacteria. Compound 6k showed potential against Candida albicans, and compound 6l showed potential against Aspergillus Niger. However, compound 6b showed poor antimicrobial activity. Compounds 6g and 6f also exhibited ferrous ion chelating activity at 28.69 μg/ml and 29.94 μg/ml, respectively.

Based on the IC50 values, it was found that only compounds 6g and 6f had superior against oxidation, which was evaluated using EDTA as a reference. The ADMET properties were analyzed using SwissADME. Furthermore, the lead likeness results showed that 6g exhibited lead-like characteristics.

Diabetic nephropathy, a complex microvascular complication of diabetes, poses substantial health and economic challenges globally. ZWD, known for its multi-component composition, has demonstrated potential therapeutic effects in DN, yet its molecular mechanisms require further elucidation to support its clinical application.

This study aimed to comprehensively investigate the active components, target molecules, and molecular mechanisms of Zhenwu Decoction (ZWD), a Traditional Chinese Medicine (TCM) formula, in the treatment of diabetic nephropathy (DN), with a focus on its anti-inflammatory effects through the modulation of the PDE3A-mediated cAMP-PKA-NFκB axis.

The primary objective was to identify the active components of ZWD, their targets, and the underlying molecular pathways through which ZWD exerts its therapeutic effects on DN, specifically focusing on the modulation of inflammation in renal cells under high glucose conditions.

A combined approach of network pharmacology, single-cell transcriptomics, and molecular docking analyses was employed to investigate the active components, target molecules, and underlying mechanisms of ZWD in treating DN. A high-glucose-induced HK-2 cell model was established to simulate in vitro DN conditions. Cell viability was assessed using the CCK-8 assay, while quantitative real-time PCR (qPCR) and Western blotting were employed to quantify gene expression and protein levels, respectively.

Our analysis uncovered 141 active components in ZWD, which targeted 171 proteins involved in pathways related to hypoxia response, neuroactive ligand-receptor interaction, urotensin II signaling, and other pathways implicated in diabetes and vascular diseases. Among these, 75 overlapping genes were pinpointed as potential therapeutic targets of ZWD for DN. Protein-protein interaction networks revealed three functional clusters of targets potentially associated with oxidative stress responses, lipid metabolism, and hormonal regulation. Cell-type specific analyses showed differential expression of these targets in DN, particularly in proximal tubular epithelial cells. Notably, through molecular docking, we discovered a strong binding affinity between PDE3A and beta-sitosterol. In vitro experiments confirmed that ZWD extract modulated PDE3A expression, leading to the suppression of the PKA/AMPK/NF-κB axis and attenuation of high glucose-induced inflammation in HK-2 cells.

This study identified that Zhenwu Decoction (ZWD) suppressed high glucose-induced inflammation in renal cells by inhibiting the PDE3A-mediated cAMP-PKA-NFκB axis, highlighting the potential of ZWD as an effective adjunct therapy for diabetic nephropathy and paving the way for innovative anti-inflammatory treatments.

Breast cancer is the most common cancer in women. Tyrosine kinase inhibitors were developed to treat breast cancer. EGFR/ErbB1 inhibition has proved to be a promising target in breast carcinoma therapy. Drugs with benzimidazole nucleus have been approved by the FDA for cancer treatment.

To design and develop benzimidazole anticancer small molecules for EGFR inhibition for the treatment of breast cancer.

By 3D-QSAR-based virtual screening, molecular docking, molecular simulation and drug likeness study.

In this research, a 3D-QSAR pharmacophore was generated with four salient features. Namely H-bond acceptor (HBA), two ring aromatic (RA) and hydrophobic (HY) features. Its correlation-coefficient (r) is 0.8412, RMSD of 0 .96 and with 32.84 bits cost difference value. With virtual screening, 4 top hits were identified. Novel benzimidazole derivatives were designed (1a-ll) by using the features of hit molecules and the pharmacophore. The novel designed small molecules that were druggable as they passed the Lipinski and Veber rule. Novel ligands and EGFR protein interaction were good. 1a and 1i were found to be the best-designed molecules. They had -8.6 Kcal/mol and -8.4 Kcal/mol docking interaction energy, respectively, whereas Compound 4 (reference) scored -7.4 Kcal/mol. Both these molecules were stable inside the binding pocket of the EGFR protein. The molecular dynamic simulation study revealed that 1a attained equilibrium at 0.15nm.

In silicon novel benzimidazole small molecules were designed and developed as EGFR inhibitors to treat breast cancer.

Intervertebral Disc Degeneration (IDD) is a major cause of lower back pain. Ginsenoside compound C (GCC) has shown potential in treating IDD, but its specific targets and mechanisms remain unclear.

This study aimed to investigate the potential molecular mechanisms of GCC in the treatment of IDD using network pharmacology and molecular docking approaches.

Public databases were utilized to identify 100 targets related to GCC and 20,757 targets associated with IDD, of which 96 common targets were determined through cross-analysis. A Protein-Protein Interaction (PPI) network was constructed using the STRING database, and key gene clusters were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore the biological processes and pathways involved. Molecular docking was conducted to verify the binding of GCC to key proteins.

Six key genes, including HSP90AA1, CASP3, MAPK1, EGFR, HIF1A, and PIK3CA, were identified as central to the PPI network. GO analysis suggested that GCC's targets are involved in intracellular processes, while KEGG analysis highlighted the IL-17 and TNF signaling pathways. Molecular docking confirmed stable binding between GCC and key proteins, with binding energies ranging from -3.58 to -2.01 Kcal/mol.

GCC may inhibit the IL-17 and TNF signaling pathways by interacting with key proteins, potentially contributing to the treatment of IDD.

Enzymes belonging to the kinase family have been extensively implicated in cancer. Aurora A (AURKA) is crucial in regulating the cell cycle. AURKA's significant role in the formation of abnormal mitotic spindles and the failure of cytokinesis positions it as a promising target for anticancer treatments. Notably, AURKA is observed to be overexpressed in various cancer types, making its inhibition a compelling strategy for the development of anticancer agents.

In this study, we set out to investigate a novel de novo design strategy aimed at developing and optimizing potent inhibitors for Aurora Kinase A. Given Aurora Kinase A's critical role in cell cycle regulation and its overexpression in various cancers, it presents a promising target for therapeutic intervention. Our goal was to create a new library of compounds, building on existing inhibitors known for their selectivity and potency against Aurora Kinase A. By making strategic modifications to these lead molecules, we aimed to improve their binding affinity and inhibitory effectiveness. This research was focused on identifying and refining compounds with enhanced drug-like properties and robust inhibitory potential, contributing to the advancement of effective anticancer therapies.

A compound library based on known inhibitors having Aurora Kinase A selectivity and IC50 value in the nanomolar range was designed by modification in the lead molecules identified by analyzing the binding mode of the molecules in the catalytic site of the enzyme. A molecular docking study was performed in GOLD 2020. Drug-likeness ADME parameters (molecular weight, H-bond acceptors, H-bond donors, LogP, and the number of rotatable bonds) of designed molecules were calculated using SwissADME, pkCSM, and ProToxII web servers.

The docking study, utilizing GOLD 2020 software on Aurora Kinase A (PDB: 3W2C), successfully identified inhibitors that hindered the enzyme's activity by occupying its catalytic site. This inhibition mechanism, consistent across all cases, involves crucial interactions with residues such as Ala213, Asp274, and Phe144. A detailed analysis of the compounds guided the design of new analogs, aiming to enhance the lead compound's affinity for the receptor. Subsequent derivatization of M1 and M15 resulted in molecules (M1_46, M1_49, M1_50, M15_21, M15_14, and M15_43) showing a notable 10-15% increase in the Chemscore fitness scoring function compared to their parent molecules. This improvement correlated with a rise in the number of hydrogen bond interactions in the complexes, guiding further development.

This computational assessment lays a foundation for further in-vitro and in-vivo studies in drug development, suggesting these derivatives as promising candidates for cancer treatment.

Post-operative adhesion band formation is a serious post-surgery complication with a highly detrimental impact on patient morbidity and health care costs. In this study, we aimed to investigate the repurposed potential of a safe and FDA-approved drug, metformin, in attenuating post-surgical adhesion band formation in Achilles tendon surgeries in an animal model.

Wistar albino rats were divided randomly into three groups: sham, positive control, and metformin-treated groups (n=6). We administered Metformin 100 mg/kg orally for 21 days. Achilles tendon tissue sections were stained with Hematoxylin-Eosin and Masson's trichrome to assess the accumulation of inflammatory cells and collagen deposition. Spectrophotometric analysis was performed on tissue samples to determine oxidative stress markers. According to Tang and Ishiyama scoring systems, Achilles tendon adhesion properties were compared.

Using the Tang and Ishiyama scoring system, we showed that metformin significantly decreased the length, density, grading, and severity of adhesion bands at surgery sites (***p<0.001). Pathologic morphological changes and oxidative stress markers decreased in tendon tissue samples of metformin-treated rats compared to control (**p<0.01, ***p<0.001). Moreover, administration of metformin markedly decreased collagen deposition, fibrosis accumulation, and fibrosis quantity score as visualized by Masson’s trichrome staining in tissue sections (*p<0.05).

These results suggest that metformin, with its potent anti-inflammatory and anti-fibrotic properties, can be repurposed as a potential therapeutic molecule for preventing post-operative adhesion band formation.

Traditional Chinese medicine rarely applies the herb Safflower (Carthamus tinctorius) to the treatment of tumors and little is known about its mechanisms and the treatment of Safflower for melanoma.

This study aims to analyze the active ingredients and underlying mechanisms of Safflower in treating melanoma using network pharmacology, molecular docking, and in vitro experiments and provide a new direction for the research and development of new drugs for melanoma treatment.

We collected the active chemical ingredients from Safflower and generated a network of “Drug-Active Ingredient-Target” by Cytoscape. From the DrugBank, OMIM, and GeneCard databases, disease-related targets of melanoma were obtained. The intersection target genes between Safflower and melanoma were identified, leading to the construction of a protein-protein interaction (PPI) network via Cytoscape software. Metascape database was used to enrich pathways for relative targets of Safflower. Molecular docking was demonstrated by the software AutoDockTools-1.5.6. Use an online database (https://xenabrowser.net/) and R package IOBR (version 0.99.9) to evaluate the correlation between the core target genes and prognosis or the immune score. CCK8 and PCR were used to detect the toxicity of quercetin on melanoma cells and its effects on mRNA expression of AKT1, JUN, and TP53.

Our investigation identified 17 active pharmaceutical ingredients within Safflower alongside 94 potential targets related to melanoma treatment. Gene Ontology (GO) analysis is primarily concerned with extracellular exosomes, positive regulation of transcription from RNA polymerase II promoter, and protein binding. KEGG pathway enrichment analysis mainly involves Pathways in cancer, IL-17 signaling pathway, AGE-RAGE signaling pathway, and other pathways. Using molecular docking, it can be seen that the compounds Quercetin, kaempferol, luteolin, baicalein, and beta-sitosterol in Safflower have strong binding abilities with important targets. The results of survival analysis and immune score analysis suggest that Safflower may regulate the immune cell infiltration of melanoma patients by acting on core target genes and improving the prognosis of patients. In vitro analysis confirmed that Quercetin was cytotoxic toward B16-F10 cells and altered mRNA expression of AKT1, JUN, and TP53 identified through the network pharmacology approach.

This work offered an active pharmaceutical ingredient in Safflower and potential targets for melanoma, and the mechanism of its action on melanoma may be related to the regulation of immune-related pathways in melanoma.