Developing 68Ga-Labeled Exendin(9-39) Derivatives for PET Imaging of Insulinomas.

Objective: This study investigates the therapeutic potential of Colony Stimulating Factor 1 Receptor (CSF1R) inhibitors in targeting neuroinflammation, focusing on the modulation of the JNK/NLRP3/IL-1β signaling pathway, a key axis contributing to neurodegenerative and neuropsychiatric diseases. Methods: In silico docking analyses were conducted to evaluate the interactions between CSF1R inhibitors and pivotal inflammatory proteins (JNK, NLRP3, IL-1β). Molecular Dynamics (MD) simulations assessed the stability and conformational dynamics of the ligand-protein complexes. The inhibitors' physicochemical and ADME profiles and toxicity characteristics were analyzed using QikProp and computational toxicity prediction tools. Results: The docking studies demonstrated that BLZ945 exhibits superior binding affinities with docking scores of-11.107 kcal/mol for JNK, -9.870 kcal/mol for NLRP3, and -4.872 kcal/mol for IL-1β, surpassing other inhibitors such as chiauranib and pexidartinib. ADME analysis revealed that BLZ945 has favorable drug-like properties, including high oral bioavailability (94.025%) and effective blood-brain barrier penetration (QPlogBB:-1.159). Toxicity evaluations confirmed its low toxicity profile, positioning it as a safer candidate compared to edicotinib and ARRY382. MD simulations further validated the stability of BLZ945 in complex with JNK and NLRP3, showing minimal root mean square deviation (RMSD: 2.38–3.55 Å) and strong hydrophobic interactions with key residues. Conclusion: The findings highlight BLZ945 as a promising CSF1R inhibitor for modulating the JNK/NLRP3/IL-1β pathway, offering potential therapeutic benefits for neuroinflammation-related disorders. Its high binding affinities, favorable ADME properties, and stable interactions in MD simulations underscore its suitability for further experimental validation in neurodegenerative disease models.

Major histocompatibility complex class I (MHC-I), a key element of the acquired immune system, plays essential roles in activating CD8+ T cells by recognizing intracellular antigens derived from pa...

gmx_RRCS: A Precision Tool for Detecting Subtle Conformational Dynamics in Molecular Simulations.

Background/Objectives: Fructose-driven metabolic disorders, such as obesity, non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and type 2 diabetes, are significant global health challenges. Ketohexokinase C (KHK-C), a key enzyme in fructose metabolism, is a promising therapeutic target. α-Mangostin, a naturally occurring prenylated xanthone, has been identified as an effective KHK-C inhibitor, prompting exploration of its analogs for enhanced efficacy. This study aimed to identify α-Mangostin analogs with improved inhibitory properties against KHK-C to address these disorders. Methods: A library of 1383 analogs was compiled from chemical databases and the literature. Molecular docking, binding free energy calculations, pharmacokinetic assessments, molecular dynamics simulations, and quantum mechani-cal analyses were used to screen and evaluate the compounds. α-Mangostin's binding affinity (37.34 kcal/mol) served as the benchmark. Results: Sixteen analogs demonstrated binding affinities superior to α-Mangostin (from -45.51 to -61.3 kcal/mol), LY-3522348 (-45.36 kcal/mol), and reported marine-derived inhibitors (from -22.74 to -51.83 kcal/mol). Hits 7, 8, 9, 13, and 15 not only surpassed these benchmarks in binding affinity, but also exhibited superior pharmacokinetic properties compared to α-Mangostin, LY-3522348, and marine-derived inhibitors, indicating strong in vivo potential. Among these, hit 8 emerged as the best performer, achieving a binding free energy of -61.30 kcal/mol, 100% predicted oral absorption, enhanced metabolic stability, and stable molecular dynamics. Conclusions: Hit 8 emerged as the most promising candidate due to its superior binding affinity, favorable pharmacokinetics, and stable interactions with KHK-C. These findings highlight its potential for treating fructose-driven metabolic disorders, warranting further experimental validation.

ObjectiveWith the aim of clarifying the therapeutic mechanisms of the American Ginseng-Achyranthes bidentata (AG&A) herbal pair in primary Sjögren’s syndrome (pSS), this study employs an integrated approach combining network pharmacology, molecular docking, molecular dynamics simulations, and animal experiments.MethodsNetwork pharmacology & LC-MS/MS was utilized to identify the active components and potential targets of A&A. Molecular docking and dynamics simulations were performed to evaluate binding affinity and complex stability with key targets. Animal experiments using non-obese diabetic (NOD) mice were conducted to validate symptom improvement by critical active components.ResultsNetwork pharmacology identified baicalin and quercetin as key active components. Molecular docking revealed strong binding affinities (binding energy ≤ -8.0 kcal/mol) between these compounds and apoptosis-related proteins, BAX and CASP3. Molecular dynamics simulations confirmed the stability of these complexes. Animal experiments demonstrated that baicalin can significantly reduce inflammatory cytokines of IL-18, TNF-α, IFN-α, and IFN-β,CXCL-10 (p < 0.05), decrease mtDNA release, and downregulate cGAS-STING pathway-related proteins including cGAS, STING, CASP3, ZBP1, TBK1, p-STING, p-TBK1, IRF3, p-IRF3 and BAX.ConclusionThe critical components baicalin and quercetin from AG&A, particularly in aqueous extracts, exhibit therapeutic efficacy against pSS. This study provides experimental evidence for their action mechanism through modulating the mtDNA-cGAS-STING pathway. While highlighting their therapeutic potential, additional in vivo and clinical studies are warranted to validate these findings.

Quorum sensing (QS) regulates bacterial functions like virulence and biofilm formation, mediated by proteins such as LasI and QscR in Pseudomonas aeruginosa. This study investigates the structural dynamics of LasI and QscR proteins in complex with Sulfamerazine and Sulfaperin, using AiiA lactonase as a negative control, through molecular dynamics (MD) simulations to identify potential QS modulators. Molecular docking and MD simulations assessed binding affinity and structural dynamics, analyzing parameters like docking scores, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), radius of gyration (Rg), principal component analysis (PCA), and covariance analysis. Sulfamerazine exhibited the highest binding affinity for LasI based on docking scores, indicating strong ligand-protein interactions. MD simulations revealed stability in the LasI-Sulfamerazine complex, with lower RMSD compared to LasI-Sulfaperin and QscR complexes. RMSF analysis indicated greater flexibility in ligand-binding regions of LasI-Sulfaperin and QscR complexes, suggesting weaker binding. SASA showed a decrease in solvent-accessible surface area for the LasI-Sulfamerazine complex, supporting a compact structure. Rg values confirmed this, with the LasI-Sulfamerazine complex being more compact (~2.00 nm) than QscR-ligand complexes (2.10–2.30 nm). PCA revealed significant conformational changes in the LasI-Sulfamerazine complex, with PC1 explaining 57.26% variance. Covariance analysis indicated stronger residue coupling in the LasI-Sulfamerazine complex, suggesting higher rigidity, while LasI-Sulfaperin and QscR complexes exhibited flexible dynamics. AiiA lactonase was used as a negative control due to its established quorum quenching activity, which hydrolyzes AHL molecules and disrupts QS signaling. Unlike LasI and QscR, AiiA does not rely on small molecule binding for activation. However, a known LasI or QscR inhibitor would have served as a more appropriate positive control, which will be considered in future studies. These findings suggest the LasI-Sulfamerazine complex’s stability and rigidity make Sulfamerazine a promising QS modulator. Computational analyses highlight its potential to disrupt bacterial communication. Further experimental validation is needed to confirm its therapeutic implications.

Quorum sensing (QS) regulates bacterial functions like virulence and biofilm formation, mediated by proteins such as LasI and QscR in Pseudomonas aeruginosa. This study investigates the structural dynamics of LasI and QscR proteins in complex with Sulfamerazine and Sulfaperin, using AiiA lactonase as a negative control, through molecular dynamics (MD) simulations to identify potential QS modulators. Molecular docking and MD simulations assessed binding affinity and structural dynamics, analyzing parameters like docking scores, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), radius of gyration (Rg), principal component analysis (PCA), and covariance analysis. Sulfamerazine exhibited the highest binding affinity for LasI based on docking scores, indicating strong ligand-protein interactions. MD simulations revealed stability in the LasI-Sulfamerazine complex, with lower RMSD compared to LasI-Sulfaperin and QscR complexes. RMSF analysis indicated greater flexibility in ligand-binding regions of LasI-Sulfaperin and QscR complexes, suggesting weaker binding. SASA showed a decrease in solvent-accessible surface area for the LasI-Sulfamerazine complex, supporting a compact structure. Rg values confirmed this, with the LasI-Sulfamerazine complex being more compact (~2.00 nm) than QscR-ligand complexes (2.10-2.30 nm). PCA revealed significant conformational changes in the LasI-Sulfamerazine complex, with PC1 explaining 57.26% variance. Covariance analysis indicated stronger residue coupling in the LasI-Sulfamerazine complex, suggesting higher rigidity, while LasI-Sulfaperin and QscR complexes exhibited flexible dynamics. AiiA lactonase was used as a negative control due to its established quorum quenching activity, which hydrolyzes AHL molecules and disrupts QS signaling. Unlike LasI and QscR, AiiA does not rely on small molecule binding for activation. However, a known LasI or QscR inhibitor would have served as a more appropriate positive control, which will be considered in future studies. These findings suggest the LasI-Sulfamerazine complex's stability and rigidity make Sulfamerazine a promising QS modulator. Computational analyses highlight its potential to disrupt bacterial communication. Further experimental validation is needed to confirm its therapeutic implications.

Ab initio-based high-throughput computing and screening are now being used to search and predict new functional materials and novel compounds. However, systematic experimental validation on the predictions remains highly challenging, yet desired. Careful comparison between computational predictions and experimental results is sparse in the literature. Here we report on a systematic experimental validation on previously presented computational predictions of a novel alkali carbonophosphate family of compounds. We report the successful hydrothermal synthesis and structural characterization of multiple sodium carbonophosphates. The experimental conditions for formation of the carbonophosphates and the computational results are compared and discussed. We also demonstrate topotactic chemical de-sodiation of one of the compounds, indicating the potential use of this novel class of compounds as Li(+) or Na(+) insertion electrodes.

Editor's evaluation: Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics

Author response: Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics

Exploring <i>Artocarpus heterophyllus</i> phytochemicals as novel mineralocorticoid receptor inhibitors: A computational approach to hypertension therapy

The escalating threat posed by the Monkeypox virus (MPXV) to global health necessitates the urgent discovery of effective antiviral agents, as there are currently no specific drugs available for its treatment, and existing inhibitors are hindered by toxicity and poor pharmacokinetic profiles. This study aimed to identify potent MPXV inhibitors by screening a diverse library of small molecule compounds derived from marine fungi, focusing on the viral protein VP39, a key methyltransferase involved in viral replication. An extensive virtual screening process identified four promising compounds—CMNPD15724, CMNPD28811, CMNPD30883, and CMNPD18569—alongside a control molecule. Rigorous evaluations, including re-docking, molecular dynamics (MD) simulations, and hydrogen bond analysis, were conducted to assess their inhibitory potential against MPXV VP39. CMNPD15724 and CMNPD30883, in particular, demonstrated a superior binding affinity and stable interactions within the target protein's active site throughout the MD simulations, suggesting a capacity to overcome the limitations associated with sinefungin. The stability of these VP39-compound complexes, corroborated by MD simulations, provided crucial insights into the dynamic behavior of these interactions. Furthermore, Principal Component Analysis (PCA) based free energy landscape assessments offered a detailed understanding of the dynamic conformational changes and energetic profiles underlying these compounds' functional disruption of VP39. These findings establish CMNPD15724, CMNPD28811, CMNPD30883, and CMNPD18569 as promising MPXV inhibitors and highlight marine fungi as a valuable source of novel antiviral agents. These compounds represent potential candidates for further experimental validation, advancing the development of safer and more effective therapeutic options to combat this emerging viral infection.

Engineering affinity of humanized ScFv targeting CD147 antibody: A combined approach of mCSM-AB2 and molecular dynamics simulations

This study evaluates radio-iodinated anastrozole ([125I]anastrozole) and epirubicin ([125I]epirubicin) for AKT1-targeted breast cancer therapy, utilizing radiopharmaceutical therapy (RPT) for personalized treatment. Through molecular docking and dynamics simulations (200 ns), it investigates these compounds' binding affinities and mechanisms to the AKT1 enzyme, compared to the co-crystallized ligand, a known AKT1 inhibitor. Molecular docking results show that [125I]epirubicin has the highest ΔGbind (-11.84 kcal/mol), indicating a superior binding affinity compared to [125I] anastrozole (-10.68 kcal/mol) and the co-crystallized ligand (-9.53 kcal/mol). Molecular dynamics (MD) simulations confirmed a stable interaction with the AKT1 enzyme, with [125I]anastrozole and [125I]epirubicin reaching stability after approximately 68 ns with an average RMSD of around 2.2 Å, while the co-crystallized ligand stabilized at approximately 2.69 Å after 87 ns. RMSF analysis showed no significant shifts in residues or segments, with consistent patterns and differences of less than 2 Å, maintaining enzyme stability. The [125I]epirubicin complex maintained an average of four H-bonds, indicating strong and stable interactions, while [125I]anastrozole consistently formed three H-bonds. The average Rg values for both complexes were ~16.8 ± 0.1 Å, indicating no significant changes in the enzyme's compactness, thus preserving structural integrity. These analyses reveal stable binding and minimal structural perturbations, suggesting the high potential for AKT1 inhibition. MM-PBSA calculations confirm the potential of these radio-iodinated compounds as AKT1 inhibitors, with [125I]epirubicin exhibiting the most favorable binding energy (-23.57 ± 0.14 kcal/mol) compared to [125I]anastrozole (-20.03 ± 0.15 kcal/mol) and the co-crystallized ligand (-16.38 ± 0.14 kcal/mol), highlighting the significant role of electrostatic interactions in stabilizing the complex. The computational analysis shows [125I]anastrozole and [125I]epirubicin may play promising roles as AKT1 inhibitors, especially [125I]epirubicin for its high binding affinity and dynamic receptor interactions. These findings, supported by molecular docking scores and MM-PBSA binding energies, advocate for their potential superior inhibitory capability against the AKT1 enzyme. Nevertheless, it is crucial to validate these computational predictions through in vitro and in vivo studies to thoroughly evaluate the therapeutic potential and viability of these compounds for AKT1-targeted breast cancer treatment.

Estrogen receptor alpha (ERα) plays a crucial role in breast cancer progression, making it a key target for selective estrogen receptor modulators (SERMs). While Raloxifene has demonstrated therapeutic efficacy, resistance and limited bioactivity in some cases necessitate the development of novel ERα inhibitors with improved pharmacological profiles. A computational drug discovery approach integrating molecular docking, molecular dynamics (MD) simulations, and quantitative structure-activity relationship (QSAR) modeling was employed to design and evaluate new ERα inhibitors. Molecular docking was performed using Glide (XP mode) to predict ligand binding affinity and interaction patterns, while MD simulations over 100 ns assessed the stability and conformational dynamics of the protein-ligand complexes. A QSAR model was developed using a dataset of 1,231 compounds from ChEMBL, incorporating XGBoost regression with optimized hyperparameters for robust predictive performance. Compounds 3b, 3a, and 4a showed notable binding affinities (−9.319, −9.121, and −8.867 kcal/mol, respectively) that are comparable to Raloxifene (−9.791 kcal/mol), suggesting their potential as effective ERα ligands primarily through pi-pi stacking with PHE-404 and hydrogen bonding with Glu 353. MD simulations demonstrated that 3a, 4a, and 4b maintained stable receptor interactions (RMSD &lt; 2.0 Å), while 3e and 4e exhibited higher fluctuations, indicating weaker engagement. The QSAR model achieved high predictive accuracy (RMSE &lt; 0.6, R² &gt; 0.8), identifying NO₂ (3d), OMe (3c), and Cl (3b) substitutions as key structural features enhancing receptor binding. This study identifies 3b, 3d, and 4b as promising lead compounds with strong binding affinity, stability, and predicted estrogen receptor activity. These findings provide a basis for further experimental validation and structural refinement to develop next-generation SERMs for ERα-positive breast cancer therapy.