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Identifying antivirals against influenza PA endonuclease with machine learning-based activity prediction, DFT optimization, and molecular dynamics simulation

Alharby TN, Alanazi M, Khan KU, Abouzied AS

Mol Divers, 2026 Apr;30(2):2511-2524.
PMID: 41264202 DOI: 10.1007/s11030-025-11403-3

Increasing concern about highly pathogenic avian influenza A (H5N1) is prompting the development of new antivirals directed toward conserved viral entities that are resistant to mutational escape. Here, at a multi-scale and precision-guided computational level, we employed a set of procedures to identify potential small-molecule inhibitors of the influenza virus PA endonuclease, a central component of the viral RNA polymerase complex responsible for cap-snatching of mRNA transcription. Through the structurally diverse drug-like dataset, we initiated structure-based virtual screens against the PA catalytic domain and received 1,500 high-affinity candidates. Top-scoring candidates were optimized using quantum mechanical density functional theory (DFT) computations and electron reactivity/orbital distribution analyses. Through re-docking of optimized geometries using DFT, lead molecules were subjected to exhaustive 1-microsecond molecular dynamics (MD) simulations and MM/GBSA binding free energy decomposition and principal component analysis (PCA) sampling of dynamic conformational topographies. Free energy surface mapping of low-energy basins and superimposition validation of pose stabilities verified sub-angstrom deviations. Significantly, 24782939 registered the least thermodynamic profile (ΔG = -45.8 kcal/mol), greatest H-bond persistence, and computed pIC50 of 8.17 using a machine-learned predictive model trained against structurally diverse chemical scaffolds. This multi-scale, integrated framework, involving atomic, energetic, and predictive scales, holds promise for translational applications of computational pipelines in antiviral discovery. Our findings nominate 24,782,939 as a highly promising inhibitor of PA endonuclease and have the potential to be developed into a next-gen therapeutic candidate against influenza A viruses.
Correlation between blood parameters in the early and later stages of pregnancy: A retrospective study

Ibrahim N, Alziyadi SH, Yaacob NM, AlGhamdi A, Alanazi M, Alfaifi J, et al.

Transfus Apher Sci, 2025 Apr;64(2):104084.
PMID: 39938453 DOI: 10.1016/j.transci.2025.104084

OBJECTIVE: Anemia is common in pregnant women and is associated with various maternal and fetal complications. However, the effect of fluctuations in hemoglobin levels during pregnancy on birth outcomes remains unclear. Therefore, we investigated the association between maternal hemoglobin levels at different stages of pregnancy and delivery outcomes.
METHODS: This retrospective study included 215 women who gave birth between 2018 and 2023. Hemoglobin levels were measured at three time points during pregnancy: first trimester (approximately 12 weeks), second trimester (13-27 weeks), and third trimester (28-36 weeks). The primary outcomes were the associations between hemoglobin levels and birth weight, birth weight Z-score, placental ratio, and placental weight. Statistical analyses were conducted to control for maternal and fetal factors and to determine the correlations between hemoglobin levels and delivery outcomes.
RESULTS: Hemoglobin levels in the first trimester were the best predictors of anemia in the third trimester (area under the curve (AUC), 0.63; sensitivity, 65 %; specificity, 65 %). Hemoglobin levels were inversely associated with birth weight, birth weight Z-score, placental ratio, and placental weight. The overall accuracy of predicting iron-deficiency anemia was high (sensitivity, 71 %; specificity, 76 %; AUC, 0.76). Significant associations were observed at p 
Fulltext Efficient Synthesis, Structural Characterization, Antibacterial Assessment, ADME-Tox Analysis, Molecular Docking and Molecular Dynamics Simulations of New Functionalized Isoxazoles

Arzine A, Hadni H, Boujdi K, Chebbac K, Barghady N, Rhazi Y, et al.

Molecules, 2024 Jul 17;29(14).
PMID: 39064944 DOI: 10.3390/molecules29143366

This work describes the synthesis, characterization, and in vitro and in silico evaluation of the biological activity of new functionalized isoxazole derivatives. The structures of all new compounds were analyzed by IR and NMR spectroscopy. The structures of 4c and 4f were further confirmed by single crystal X-ray and their compositions unambiguously determined by mass spectrometry (MS). The antibacterial effect of the isoxazoles was assessed in vitro against Escherichia coli, Bacillus subtilis, and Staphylococcusaureus bacterial strains. Isoxazole 4a showed significant activity against E. coli and B. subtilis compared to the reference antibiotic drugs while 4d and 4f also exhibited some antibacterial effects. The molecular docking results indicate that the synthesized compounds exhibit strong interactions with the target proteins. Specifically, 4a displayed a better affinity for E. coli, S. aureus, and B. subtilis in comparison to the reference drugs. The molecular dynamics simulations performed on 4a strongly support the stability of the ligand-receptor complex when interacting with the active sites of proteins from E. coli, S. aureus, and B. subtilis. Lastly, the results of the Absorption, Distribution, Metabolism, Excretion and Toxicity Analysis (ADME-Tox) reveal that the molecules have promising pharmacokinetic properties, suggesting favorable druglike properties and potential therapeutic agents.

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