Current Computer - Aided Drug Design - Online First

Inflammation is a natural process; however, chronic inflammation may result in numerous health issues. Etoricoxib (ETX), a selective cyclooxygenase-2 (COX-2) inhibitor, serves as an anti-inflammatory agent for various types of arthritis. However, prolonged use of ETX is associated with several adverse effects, including cardiovascular toxicity.

The current research aims to design analogues of ETX having superior pharmacokinetic properties and safer toxicological profiles employing the bioisosteric approach.

The bioisosteres of various groups in ETX were produced utilizing the MolOpt online tool, resulting in the generation of novel ETX analogues. The pharmacokinetics (ADME) and toxicological profiles of the generated analogues were calculated by ADMETLab 3.0 server. The druglikeness (DL) and drugscore (DS) were calculated using OSIRIS property explorer (PEO). The molecular docking analysis of the ETX analogues against the target protein (PDB ID: 5KIR) was carried out using AutoDock Vina, and their results were visualized by Discovery Studio 2021. Molecular dynamics (MD) simulation of the top three complexes was conducted using the Schrödinger suite. Binding free energy for the A098-5KIR, A188-5KIR, and D121-5KIR complexes was conducted using MM-GBSA/PBSA method.

A total of 1200 ETX bioisosteres were produced; among them, 51 were screened on the basis of ADMET profile, DL, and DS scores and selected for the docking study. A docking study revealed that 12 analogues show good interactions and docking scores. Furthermore, the MD simulation of ligands A098, A188, and D121 demonstrated stability throughout the 100 ns simulation period.

The findings of the ADMET study, DL, DS, docking study, MD simulation, and binding free energy calculation indicate that the analogues A098, A188, and D121, which are bioisosteres of ETX, may serve as potential anti-inflammatory agents for inflammation-related disorders.

Chemotherapy remains a primary treatment for stopping cancer cell growth. Unfortunately, resistance to chemotherapy is a challenge that leads to cancer relapse. Overexpression of the antiapoptotic proteins is a major cause of this resistance. BH3 mimetic compounds were developed in this work to deal with this issue by blocking the Bcl-2 anti-apoptotic proteins. Currently, only a few BH3 mimetics are approved drugs, and even fewer can effectively target all antiapoptotic Bcl-2 proteins.

The present study aimed to explore and screen the prodiginine family of molecules for new potential and effective BH-3 mimetics.

Molecular docking and molecular dynamics (MD) simulations were used to assess the potential of 30 prodiginine analogs as BH3 mimetics, including the obatoclax molecule, a prodiginine member used in clinical trials as a BH3 mimetic.

Molecular docking results showed four prodiginines to have lower free binding energy values for five Bcl-2 proteins (Bcl-2, Mcl-1, Bcl-w, Bcl-xl, and Bfl1) compared to the reference drug, obatoclax. The five analogs presented safe pharmacological profiles according to Lipinski’s rule of five. Furthermore, MD simulations demonstrated butylcycloheptyl prodiginine-Bcl-2 and prodigiosin-R2-Bcl-xl complexes to be more stable than the reference complexes obatoclax-Bcl-2 and obatoclax-Bcl-xl.

Based on these results, butylcycloheptyl prodigiosin and prodigiosin-R2 could be more effective BH3 mimetics and should be further studied.

XueFuZhuYu pills (XFZY), a traditional Chinese herbal formula originated from the xuefuzhuyu decoction in Correction on Errors in Medical Classics, has a certain clinical effect on the treatment of hyperprolactinemia (HPRL) caused by antipsychotics. However, the active ingredients and mechanism by which XFZY contributes to the hyperprolactinemia caused by antipsychotics remain unclear.

The aim of the study was to investigate the molecular basis of XFZY in the therapy of antipsychotic-induced HPRL and to establish a scientific foundation for its application.

First, the UHPLC-Q-TOF-MS/MS methodology was employed to perform chromatographic separation and gather mass spectrometry data. Subsequently, the preprocessed mass spectrometry data were uploaded to the Global Natural Products Social Molecular Networking (GNPS) platform for spectral library interrogation and molecular network analysis. Next, based on the detected chemical constituents and the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, the effective chemical components within XFZY were chosen. Swiss Target Prediction was employed to determine probable targets of components, and we used Cytoscape to create a network of components and their associated targets. After that, HPRL-related targets were found and filtered using four disease databases, and then a protein-protein interaction (PPI) network was built using the STRING database. Cytoscape was utilized to conduct visualization and cluster analysis. Meanwhile, the Metascape database was adopted for the enrichment analysis of GO and KEGG. At last, Autodock Vina was applied to perform molecular docking between the principal components and target proteins.

In total, 213 compounds were discovered in XFZY. Two hundred eight active chemical components, 622 probable targets, and 242 HPRL-related target genes were identified. There were 76 common targets between the XFZY and HPRL. Following analysis, 1371 GO biological process items and 162 KEGG signal pathways were identified. The primary chemicals and target proteins exhibited great affinity in molecular docking.

This research manifests that XFZY, as a traditional Chinese medicine formula, proffers a novel pathway for the treatment of antipsychotic-induced HPRL. We elucidated the specific molecular mechanisms underlying the anti-HPRL effects of XFZY and its active ingredients, laying a foundation for the subsequent clinical applications of this formula.

Our group previously reported isatin-based hydrazones (ISB1-ISB6) were further evaluated for their in vitro acetylcholine esterase, butylcholinestrase and cytotoxic effects on cancer cell lines. The compounds successfully suppressed AChE and BChE, with Ki values ranging from 1.06±0.07 to 23.57±1.64 nM for AChE and 15.31±1.28 to 84.41±8.04 nM for BChE. However, the IC50 values of these compounds for AChE and BChE were found to be in the ranges of 1.45-25.51 nM and 16.38-92.90 nM, respectively.

Furthermore, to explore the anti-tumor potential of our newly synthesized compounds, we conducted a cytotoxic MTT assay to assess their impact on two different cancer cell lines: MCF7 and A2780.

Our findings highlight diverse cytotoxic profiles among the compounds. Specifically, ISB2, ISB3, and ISB4 demonstrated potential cytotoxicity in the A2780 cell line, while ISB6 exhibited significant cytotoxicity in the MCF7 cell line. This suggests that these compounds have different effects on cancer cell types, indicating the need for further investigation into their potential applications in cancer therapy.

Finally, molecular docking and dynamic study revealed that lead molecule ISB3 provides stability in the AChE and BChE protein-ligand complex.

An important characteristic of the quality-by-design approach is defining risk, which is a combination of the probability of harm and its severity. During risk assessment, it is essential to determine how the formulation, properties of active ingredients and excipients, and process parameters can potentially affect critical quality attributes or critical process parameters.

to develop an algorithm and a mathematical model for predicting quality risks in the pharmaceutical development of bisoprolol fumarate tablets with indapamide.

The software programs “Microsoft Excel 2016” and “Statistica 10.0” (StatSoft, Inc.) were used to predict potential risks and to build a regression model of quality-related risks for bisoprolol fumarate tablets with indapamide.

A mathematical model for predicting the tablet quality risk has been developed, incorporating significant predictors: Carr's index for powder mixtures (Х1), evaluation of the pressing process (Х2), uniformity of tablet weight (Х3), tablets hardness testing (Х4), disintegration time (Х6). Four levels of quality risk are defined: low risk [0.8-1.0], moderate risk [0.6-0.8], high risk [0.4-0.6], and critical risk [0-0.4]. The calculated coefficient of determination of the forecasting model (R²=0.8168) testifies to its high quality.

The developed algorithm and mathematical model for predicting tablet quality risks are highly informative and qualitative. The proposed approach represents an innovative and promising tool for assessing and predicting risks associated with the quality of medicinal products, particularly during the early stages of pharmaceutical development.

The potency content of penicillin serves as a crucial indicator for measuring its pharmacological effects, playing a vital role in quality control and clinical applications. In recent years, with the continuous improvement of production efficiency and quality requirements in the pharmaceutical industry, the need for high-frequency monitoring of drug potency has become increasingly urgent. Infrared spectroscopy, as an emerging research tool, has demonstrated immense potential in the field of drug potency testing.

The objective of this study is to develop a real-time monitoring model for penicillin potency content utilizing near-infrared (NIR) spectroscopy data. This model aims to enable rapid and accurate detection of potency content during the penicillin production process, ultimately enhancing production efficiency and reducing costs.

During the penicillin production process, NIR spectroscopy data from penicillin samples were scanned and collected to form a comprehensive dataset. Five distinct spectral preprocessing methods were combined with three regression models to construct detection models. By comparing the performance of different combinations, the optimal model configuration was identified.

The optimal model configuration identified in this study integrates the Savitzky-Golay filtering method with ridge regression. Under this optimal model, the coefficient of determination for the test set reached 0.990669, indicating an extremely high degree of agreement between the model's predicted values and the actual measured values. This real-time monitoring model for penicillin potency content can be applied as a rapid and non-destructive monitoring method in factory settings.

This study successfully developed a real-time monitoring model for penicillin potency based on NIR spectroscopy technology. The research findings not only provide strong support for potency monitoring during the penicillin production process but also offer new insights and methodologies for non-destructive testing of other pharmaceuticals and chemicals.

Thermolabile hemolysin (TLH) is a key virulent protein of Vibrio alginolyticus, known for its hemolytic and phospholipase activities, leading to shrimp vibriosis disease. It has been suggested as a potential therapeutic candidate for vibriosis therapy.

Computational studies, including molecular docking, toxicity analysis, and molecular dynamics (MD) simulations, were conducted to investigate the inhibition of the phospholipase activity of TLH by phytochemicals from Emblica officinalis.

Out of the twenty-nine compounds, the top three, including Ellagic acid (CID 5281855), Quercetin (CID 5280343), and Kaempferol (CID 5280863), were sorted based on their highest molecular docking scores of -9.2, -8.9, and -8.8, respectively. Subsequently, molecular dynamics (MD) simulations of these selected leads were performed to observe the structural stability of these compounds in the binding sites of TLH protein. The MD simulation outcomes indicated that all three compounds demonstrated superior stability throughout 100 nanoseconds compared to the control compound Resveratrol. The molecular simulation results suggest stable interactions, with average root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) values of 1-2 Å and 0-3 Å. Pharmacokinetic and toxicity analyses were conducted to evaluate the suitability and toxicity of these selected compounds. All top three compounds passed the Lipinski rule, and toxicity criteria.

Therefore, these compounds have the potential to serve as effective therapeutics for controlling Vibrio alginolyticus infection in shrimp.

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.