Current Computer - Aided Drug Design - Online First

The function of HOXC antisense RNA 1 (HOXC-AS1) in lung adenocarcinoma (LUAD) remains largely unexplored.

The objective of this research was to examine the relationship between HOXC-AS1 levels and LUAD through both bioinformatics analysis and experimental validation.

We employed statistical methods and bioinformatics to evaluate the correlation between HOXC-AS1 expression and various clinical features, survival predictors, regulatory mechanisms, and immune cell infiltration in LUAD. The levels of HOXC-AS1 in LUAD cell lines were ascertained through quantitative reverse transcription PCR.

HOXC-AS1 displayed significantly increased expression in individuals with LUAD. There was a significant correlation between high HOXC-AS1 levels and diminished overall survival in LUAD patients, characterized by a hazard ratio of 0.66, a 95% confidence interval of 0.49 to 0.88, and a statistically significant P-value (0.005). An elevated expression of HOXC-AS1 was found to be a standalone predictor of poor overall survival in LUAD patients, with a P-value of 0.002. HOXC-AS1 was found to be implicated in various pathways, such as neuroactive ligand-receptor interaction and asthma, among others. The study revealed a substantial link between high HOXC-AS1 expression and unfavorable outcomes in LUAD, including poor survival and altered immune cell infiltration. LUAD cell lines exhibited a marked increase in HOXC-AS1 expression compared to the Beas-2B normal lung cell line.

The research indicated a strong association between higher levels of HOXC-AS1 and negative outcomes in LUAD, such as reduced survival rates and the presence of immune cell infiltration. HOXC-AS1 could potentially be utilized as a biomarker to anticipate patient prognosis and their likelihood of responding to immunotherapies in LUAD.

The extended IL-1 activity is implicated in autoimmune disorders, such as rheumatoid arthritis, diabetes mellitus, and Parkinson's disease, as well as delayed wound healing. Additionally, it can result in cytokine storms during pathogenic infections.

The regulation was carried out by Interleukin-1 receptor antagonist (IL-1RA), a key anti-inflammatory molecule. IL-1RA serves as a decoy protein that competes with Interleukin-1 receptors (IL-1RI and IL-1RII) for binding, effectively counteracting the activity of Interleukin-1 (IL-1). The deficiency was substantiated by commercially available recombinant IL-1RA called Anakinra. The main problem with the existing drug is that it has less pharmacokinetics and reduced binding affinity to its receptor, which requires frequent administration of the drug. To overcome these drawbacks, we have designed a new fusion protein by adding an Fc fragment of Human IgGI fused with IL-1RA using a linker in between, and the design aimed to transport the protein into the N-glycosylation pathway. These characteristic features increase the pharmacokinetics, solubility, and binding efficiency of the protein. As the protein was designed to be expressed in a eukaryotic system, to understand the possibility of the proposed hypothesis, we used machine learning-based AlphaFold2 to model the protein structure and molecular simulation studies to understand the functional integrity of the designed protein.

The in silico results showed that the modeled fusion protein structure has very good binding to its receptor with the support of 21 H bonds and 7 salt bridges and maintained the binding stability over the MD simulations.

These findings support fusion protein’s potential as a promising and stable therapeutic candidate.

Qi-Gui-Jian-Gu decoction (QGJG), as a clinical empirical formula, has clinical benefits in promoting bone formation, but the underlying mechanism for its application in treating fractures has not been investigated.

The potential therapeutic target and signaling pathway of QGJG for treating fractures were analyzed by network pharmacology. In vitro, we used bone marrow mesenchymal stem cells (MSCs) to evaluate osteogenic differentiation and mineralization by alizarin red staining, quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB), and immunofluorescence staining. In vivo, the 8w male SPF C57BL/6J mouse femoral fracture model was constructed, and the therapeutic effects of QGJG were evaluated.

By network pharmacology analysis, we found that glycogen synthase kinase 3 beta (GSK3β) was a potential therapeutic target of QGJG for treating fractures. The canonical Wnt signaling pathway was selected as the potential molecular mechanism. QGJG was confirmed to upregulate the mRNA levels of alkaline phosphatase (ALP) and bone morphogenetic protein 2 (BMP2), thereby promoting osteogenic differentiation and mineralization. Mechanistically, QGJG inhibited GSK3β while increasing p-Ser9-GSK3β to increase β-catenin protein expression and its nuclear translocation, implying the activation of the canonical Wnt signaling pathway. In vivo, QGJG administration promoted fracture healing, as demonstrated by the up-regulation of OPN and Osx, and accelerated the progression of ossification at 2 and 3 weeks after surgery.

QGJG promotes osteogenic differentiation and fracture healing by activating the canonical Wnt pathway.

Astrocytoma is the most common glioma, accounting for about 65% of glioblastoma. Its malignant transformation is also one of the important causes of patient mortality, making it the most prevalent and difficult to treat in primary brain tumours. However, little is known about the underlying mechanisms of this transformation.

In this study, we established a ceRNA network to screen out the potential regulatory pathways involved in the malignant transformation of IDH-mutant astrocytomas. Firstly, the Chinese Glioma Genome Atlas (CGGA) was employed to compare the expression levels of the differential expressed genes (DEGs) in astrocytomas. Then, the ceRNA-regulated network was constructed based on the interaction of lncRNA-miRNA-mRNA. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore the main functions of the differentially expressed genes. COX regression analysis and log-rank test were combined to screen the ceRNA network further. In addition, quantitative real-time PCR (qRT-PCR) was conducted to identify the potential regulatory mechanisms of malignant transformation in IDH-mutant astrocytoma.

A ceRNA network with 34 lncRNAs, 29 miRNAs, and 71 mRNAs. GO and KEGG analyses results suggested that DEGs were associated with tumor-associated molecular functions and pathways. In addition, we screened two ceRNA regulatory networks using Cox regression analysis and log-rank test. QRT-PCR assay identified the NAA11/hsa-miR-142-3p/GS1-39E22.2 regulatory axis of the ceRNA network to be associated with the malignant transformation of IDH-mutant astrocytoma.

The discovery of this mechanism deepens our understanding of the molecular mechanisms of malignant transformation in astrocytomas and provides new perspectives for exploring glioma progression and targeted therapies.

Research has elucidated that the pathophysiological underpinnings of non-alcoholic fatty liver disease and type 2 diabetes mellitus are intrinsically linked to insulin resistance (IR). However, there are currently no pharmacotherapies specifically approved for combating IR. Although Alpinia officinarum Hance (A. officinarum) can ameliorate diabetes, the detailed molecular mechanism through which it influences IR has not been fully clarified.

To predict the active components of A. officinarum and determine the mechanism by which A. officinarum affects IR.

The active compounds and molecular mechanism underlying the improvement of IR by A. officinarum were predicted via network pharmacology and molecular docking. To further substantiate these predictions, an in vitro model of IR was induced in HepG2 cells using high glucose concentrations. Cytotoxicity and oxidative stress levels were evaluated using Cell Counting Kit-8, reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) assay kits. The putative molecular mechanisms were corroborated through Western blot and RT-PCR analyses.

Fourteen principal active components in A. officinarum, 133 potential anti-IR gene targets, and the top five targets with degree values were ALB, AKT1, TNF, IL6, and VEGFA. A. officinarum was posited to exert its pharmacological effects on IR through mechanisms involving lipid and atherosclerosis, the AGE-RAGE signaling pathway in diabetic complications, the PI3K-AKT signaling pathway, fluid shear stress, and atherosclerosis. Intriguingly, network pharmacology analysis highlighted (4E)-7-(4-hydroxy-3-methoxyphenyl)-1-phenylhept-4-en-3-one (A14) as the most active compound. Molecular docking studies further confirmed that A14 has a strong binding affinity for the main targets of PI3K, AKT, and Nrf2. The experiments demonstrated that A14 significantly diminished the ROS and MDA levels while augmenting the SOD activity. Moreover, A14 was found to elevate the protein expression of PI3K, AKT, Nrf2, and HO-1, and increase the mRNA levels of these targets as well as NQO1.

A. officinarum could play a therapeutic role in IR through multiple components, targets, and pathways. The most active component of A. officinarum responsible for combating IR is A14, which has the ability to regulate oxidative stress in IR-HepG2 cells by activating the PI3K/AKT/Nrf2 pathway. These findings suggest a potential pharmacological intervention strategy for the treatment of IR.

Kushen (Sophora flavescens Ait.) has a long history of medicinal use in China due to its medicinal values, such as antibacterial, antiviral, and anti-inflammatory. Rapid discovery of the components and the medicinal effects exerted by Kushen will help elucidate the science of Kushen in curing diseases. GSK3β (glycogen synthase kinase-3 beta) is a protein kinase with a wide range of physiological functions, such as antibacterial, antiviral, and anti-inflammatory. The discovery of inhibitors targeting GSK3β from Kushen was not only helpful for the rapid discovery of the components responsible for the efficacy of Kushen but also important for the development of novel drugs.

In this study, the chemical composition of Kushen was extracted from the TMSCP database. Molecular docking, GSK3β enzyme assay, and molecular dynamics simulations were used to discover the GSK3β inhibitors from the chemical composition of Kushen.

A total of 113 chemical compositions of Kushen were extracted from the TMSCP database. Molecular docking indicated that 15 chemical compositions of Kushen scored better than -8 kcal/mol against GSK3β. GSK3β enzyme assay demonstrated several inhibitory activities of kushenol I and kushenol F with IC50 values of 7.53 ± 2.55 µM and 4.96 ± 1.29 µM, respectively. Molecular dynamics simulations were used to reveal the interactions of kushenol I and kushenol F with GSK3β from structural and energetic perspectives.

Kushenol I and kushenol F could be the material basis for the antibacterial, antiviral, and anti-inflammatory properties of Kushen.

To Discover novel PTP1B inhibitors by high-throughput virtual screening

Type 2 Diabetes is a significant global health concern. According to projections, the estimated number of individuals affected by the condition will reach 578 million by the year 2030 and is expected to further increase to 700 million deaths by 2045. Protein Tyrosine Phosphatase 1B is an enzymatic protein that has a negative regulatory effect on the pathways involved in insulin signaling. This regulatory action ultimately results in the development of insulin resistance and the subsequent elevation of glucose levels in the bloodstream. The proper functioning of insulin signaling is essential for maintaining glucose homeostasis, whereas the disruption of insulin signaling can result in the development of type 2 diabetes. Consequently, we sought to utilize PTP1B as a drug target in this investigation.

The purpose of our study was to identify novel PTP1B inhibitors as a potential treatment for managing type 2 diabetes.

To discover potent PTP1B inhibitors, we have screened the Maybridge HitDiscover database by SBVS. Top hits have been passed based on various drug-likeness rules, toxicity predictions, ADME assessment, Consensus Molecular docking, DFT, and 300 ns MD Simulations.

Two compounds have been identified with strong binding affinity at the active site of PTP1B along with drug-like properties, efficient ADME, low toxicity, and high stability.

The identified molecules could potentially manage T2DM effectively by inhibiting PTP1B, providing a promising avenue for therapeutic strategies.

As a traditional Chinese medicine, Danshen shows potential efficacy for treating ulcerative colitis (UC). However, the bioactive components and mode of action were unclear.

This paper uses a combination of network pharmacology, serum medicinal chemistry, and gene expression profiling to clarify its possible molecular mechanism of action and material basis.

Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was utilized to analyze the herbal components and metabolites from the serum of Danshen-treated mice. Gene expression profiles were applied to construct a database of Danshen action targets. Then, active ingredient-target-biological functional module networks were constructed to analyze the mechanism of action. Molecular docking has further confirmed the possibility of its components to the targets.

As a result, 193 common targets between 1684 Danshen-related DEGs and 1492 UC targets were determined as the potential targets for Danshen in treatment with UC. Serum pharmacochemistry and target prediction showed that 22 components in serum acted on 777 targets. Intersection with common targets yielded 46 core targets, and an active ingredient-target-biological functional module network was constructed for analysis. Network prediction and molecular docking results showed that the main action modules were inflammatory response and cell apoptosis, which mainly acted on targets SRC, RELA, HSP90AA1, CTNNB1, STAT3, and CASP3. The main components of Danshen intervention in UC were predicted to include Catechol, 3,9-Dimethoxypterocarpan, 8-Prenylnaringenin, Isoferulic acid, Salvianolic acid C, and Danshensu.

The present study provides a scientific foundation for further explicating the mechanisms of Danshen against UC.