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Daily Signal March 19, 2026 · 8 min read

Issue #71: Design, Synthesis, Molecular Dynamics Simulations, and Biological Evaluation of PB2 Inhibitors as Anti-Influenza A Virus Agent.

Protein Design Digest - 2026-03-19 - Mechanisms of Okanin against wound healing based on network pharmacology, molecular docking and molecular dynamics simulation.

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Design, Synthesis, Molecular Dynamics Simulations, and Biological Evaluation of PB2 Inhibitors as Anti-Influenza A Virus Agent.

Influenza A virus continues to pose a significant global health threat, causing seasonal epidemics and occasional pandemics. Viral transcription and replication rely on the heterotrimeric polymerase complex where the PB2 subunit initiates RNA synthesis through binding to the host mRNA cap structure. In this study, we began with a structure-activity relationship analysis of the pioneering PB2 inhibitor VX-787. Through computer-aided drug design, combined with considerations of molecular docking scores, ADMET property predictions, and a prodrug esterification strategy, we ultimately designed eight novel compounds. Cytopathic effect assays demonstrated that all compounds exhibited superior inhibitory activity against both H1N1 and H3N2 strains compared to oseltamivir acid. In particular, compounds 11 and 15 displayed nanomolar-level activity against H1N1, while compound 18 showed activity against H3N2 superior to that of VX-787. These findings propose a rational design strategy that may offer new avenues for addressing the resistance and metabolic limitations associated with VX-787 and hold potential for advancing the development of next-generation PB2-targeted anti-influenza therapeutics.

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Also Worth Reading

Integrative gene target mapping, RNA sequencing, in silico molecular docking, ADMET profiling and molecular dynamics simulation study of marine derived molecules for type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is a metabolic disease leading threat to human health around the world. Here we aimed to explore new biomarkers and potential therapeutic targets in T1DM through adopting integrated bioinformatics tools. The gene expression Omnibus (GEO) database was used to obtain next generation sequencing data (GSE270484) of T1DM and normal control samples. Furthermore, differentially expressed genes (DEGs) were screened using the DESeq2 package in R bioconductor package. Gene Ontology (GO) and pathway enrichment analyses were performed by g:Profiler. The protein-protein interaction (PPI) network was plotted with IID PPI database and visualized using Cytoscape. Module analysis of the PPI network was done using PEWCC. Then, microRNAs (miRNAs) and transcription factors (TFs) in T1DM were screened out from the miRNet and NetworkAnalyst database. Then, the miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed by Cytoscape software. Moreover, a drug-hub gene interaction network of the hub genes was constructed and predicted the drug molecule against hub genes. The receiver operating characteristic (ROC) curves were generated to predict diagnostic value of hub genes. Finally we performed molecular docking, ADMET profiling and molecular dynamics simulation studies of marine derived chemical constituents using Schrodinger Suite 2025-1. A total of 958 DEGs were screened: 479 up regulated genes and 479 down regulated genes. DEG were mainly enriched in the terms of developmental process, membrane, cation binding, response to stimulus, cell periphery, ion binding, neuronal system and metabolism. Based on the data of protein-protein interaction (PPI), the top 10 hub genes (5 up regulated and 5 down regulated) were ranked, including FN1, GSN, ADRB2, CEP128, FLNA, CD74, EFEMP2, POU6F2, P4HA2 and BCL6. The miRNA-hub gene regulatory network and TF-hub gene regulatory network showed that hsa-mir-657, hsa-miR-1266-5p, NOTCH1 and GTF3C2 might play an important role in the pathogenesis of T1DM. The drug-hub gene interaction network showed that Clenbuterol, Diethylstilbestrol, Selegiline and Isoflurophate predicted therapeutic drugs for the T1DM. Molecular docking and molecular dynamics simulation study revealed that CMNPD5805 and CMNPD30286 as potential inhibitors of FN1 (pdb id: 3M7P) a key biomarker in pathogenesis of T1DM. These findings promote the understanding of the molecular mechanism and clinically related molecular targets for T1DM.

Innovative integration of molecular docking and machine learning for drug discovery: from virtual screening to nanomolar inhibitors.

This review highlights our group’s systematic approach to integrating molecular docking, pharmacophore modeling, and machine learning methodologies for the rational discovery of bioactive leads. We describe innovative strategies including docking-based data augmentation, ligand-receptor contact fingerprints, genetic algorithm-guided feature selection, and SHAP-based model interpretation. These approaches have enabled the discovery of nanomolar inhibitors against multiple therapeutic targets including STAT3, TTK, LSD-1, and HER2. The presented workflow demonstrates how machine learning (ML) can be synergistically combined with traditional computer-aided drug design methods to achieve efficient scaffold hopping and identify novel chemotypes with potent biological activities.

Evaluation of drug-excipient compatibility of ibuprofen with eggshell-derived calcium citrate using FTIR, DSC, and molecular docking studies.

Eggshells hold long-lasting nutritional and medicinal relevance in African folklore, often administered traditionally in its crushed or powdered form to ameliorate bone issues, treat calcium deficiency, and promote well-being. However, not much has been achieved in translating this folklore practice into pharmaceutical exploration and formulation science. Drug-excipient incompatibilities are critical considerations in the development of stable and effective pharmaceutical formulations. This study investigated the compatibility of ibuprofen with eggshell-derived calcium citrate using Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and molecular docking approaches. Calcium citrate was prepared from chicken eggshells via reaction with citric acid and characterised. Binary mixtures of ibuprofen and calcium citrate were evaluated for potential interactions using FTIR and DSC. In silico molecular docking studies were conducted using AutoDock Vina, and docking methodology was validated using re-docking of a known ibuprofen-calcium interaction. FTIR spectra of the binary mixtures showed minor peak shifts, particularly at 1710 cm -1 (C=O) and 3300 cm -1 (O-H), suggesting weak physical interactions. DSC thermograms demonstrated slight broadening and depression of the ibuprofen melting endotherm, indicating no significant incompatibility. Molecular docking revealed a binding affinity of - 4.7 kcal/mol, primarily mediated by ionic interactions between ibuprofen’s carboxyl group and calcium ions. Ibuprofen exhibits acceptable compatibility with eggshell-derived calcium citrate. These findings suggest its potential as a sustainable and cost-effective pharmaceutical filler in oral drug formulations.

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Spectroscopic and molecular docking studies of coumarin derivatives with HSA: bilirubin displacement and theranostic potential.

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Exploring the Anti-Inflammatory Mechanism of Boletus edulis Based on UPLC-MS/MS Combined With Network Pharmacology, Molecular Docking, and Experimental Validation.

To explore the material basis and mechanism of the anti-inflammatory compounds in Boletus edulis, its ethyl acetate extract was analyzed by UPLC-MS/MS. Read more →

Rational design and synthesis of Co(ii), Ni(ii) and Cu(ii) complexes bearing 1,2,4-triazole scaffold for biological applications.

The chemistry of 1,2,4-triazole-incorporating compounds and their metal complexes has attracted widespread attention due to their potential therapeutic activities. Read more →

Combined Analysis of Network Toxicology and Multiomics Revealed the Potential Mechanism of Mancozeb-Induced Hepatotoxicity in Mice Offspring.

Mancozeb (MCZ), a broad-spectrum dithiocarbamate fungicide, raises significant concerns regarding its potential hepatotoxicity. Read more →

Uncovering the therapeutic mechanism of Baicalein in diabetic retinopathy through ferroptosis regulation.

Background: Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults. Read more →

Design, Synthesis, Molecular Dynamics Simulations, and Biological Evaluation of PB2 Inhibitors as Anti-Influenza A Virus Agent.

Influenza A virus continues to pose a significant global health threat, causing seasonal epidemics and occasional pandemics. Read more →

Targeting Protein Tyrosine Phosphatase 1B (PTP1B) to Improve Insulin Sensitivity Using Indole-Fused Glycyrrhetinic Acid Conjugates with Amino Acids.

Protein Tyrosine Phosphatase 1B (PTP1B) is a crucial enzyme that significantly modulates insulin and leptin signaling, making it a highly promising target for the treatment of type 2 diabetes (T2D). Read more →

Shaping opioid conversion education in the specialist palliative care setting: a pilot study of staff experiences.

An essential skill for working within specialist palliative care is an ability to convert opioid medications. Read more →

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The protein structure is the language of life; design is its poetry. — Recep Adiyaman

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