Search Results (15)

Series of pyrene-labeled diols (Py₂-DOs) and polyols (Py-POs) were synthesized by coupling a number (n_PyBA) of 1-pyrenebutyric acids to diols and polyols to yield series of end-labeled linear (n_PyBA = 2) and branched (n_PyBA > 2) oligomers, respectively. Pyrene excimer formation (PEF) between an excited and a ground-state pyrene was studied for the Py₂-DO and Py-PO samples by analyzing their fluorescence spectra and decays in tetrahydrofuran, dioxane, N,N-dimethylformamide, and dimethyl sulfoxide. Global model-free analysis (MFA) of the pyrene monomer and excimer fluorescence decays yielded the average rate constant (<k>) for PEF. After the calculation of the local pyrene concentration ([Py]_loc) for the Py₂-DO and Py-PO samples, the <k>-vs.-[Py]_loc plots were linear in each solvent, with larger and smaller slopes for the Py₂-DO and Py-PO samples, respectively, resulting in a clear kink in the middle of the plot. The difference in slope was attributed to a bias for PEF between pyrenes close to one another on the densely branched Py-PO constructs resulting in lower apparent [Py]_loc and <k> values. This study illustrated the ability of PEF to probe how steric hindrance along a main chain affects the dynamic encounters between substituents in multifunctional oligomers such as diols and polyols. Full article

The permanent magnet synchronous motor (PMSM) is a critical device that converts kinetic energy into mechanical energy. However, it faces issues such as nonlinearity, time-varying uncertainties, and external disturbances, which may degrade the system control performance. To address these challenges, this paper proposes a prescribed performance model-free adaptive fast integral terminal sliding mode control (PP-MFA-FITSMC) method. This approach replaces conventional techniques such as parameter identification, function approximation, and model reduction, offering advantages such as quantitative constraints on the PMSM tracking error, reduced chattering, strong disturbance rejection, and ease of engineering implementation. The method establishes a compact dynamic linearized data model for the PMSM system. Then, it uses a discrete small-gain extended state observer to estimate the composite disturbances in the PMSM online, effectively compensating for their adverse effects. Meanwhile, an improved prescribed performance function and error transformation function are designed, and a fast integral terminal sliding surface is constructed along with a discrete approach law that adaptively adjusts the switching gain. This ensures finite-time convergence of the control system, forming a model-free, low-complexity, high-performance control approach. Finally, response surface methodology is applied to conduct a sensitivity analysis of the controller’s critical parameters. Finally, controller parameter sensitivity experiments and comparative experiments were conducted. In the parameter sensitivity experiments, the response surface methodology was employed to design the tests, revealing the impact of individual parameters and parameter interactions on system performance. In the comparative experiments, under various operating conditions, the proposed strategy consistently constrained the tracking error within ±0.0028 rad, demonstrating superior robustness compared to other control methods. Full article

Additive manufacturing of pharmaceutical formulations offers advanced micro-structure control of oral solid dose (OSD) forms targeting not only customised dosing of an active pharmaceutical ingredient (API) but also custom-made drug release profiles. Traditionally, material extrusion 3D printing manufacturing was performed in a two-step manufacturing process via an intermediate feedstock filament. This process was often limited in the material space due to unsuitable (brittle) material properties, which required additional time to develop complex formulations to overcome. The objective of this study was to develop an additive manufacturing MicroFactory process to produce an immediate release (IR) OSD form containing 250 mg of mefenamic acid (MFA) with consistent drug release. In this study, we present a single-step additive manufacturing process employing a novel, filament-free melt extrusion 3D printer, the MicroFactory, to successfully print a previously ‘non-printable’ brittle Soluplus^®-based formulation of MFA, resulting in targeted IR dissolution profiles. The physico-chemical properties of 3D printed MFA-Soluplus^®-D-sorbitol formulation was characterised by thermal analysis, Fourier Transform Infrared spectroscopy (FTIR), and X-ray Diffraction Powder (XRPD) analysis, confirming the crystalline state of mefenamic acid as polymorphic form I. Oscillatory temperature and frequency rheology sweeps were related to the processability of the formulation in the MicroFactory. 3D printed, micro-structure controlled, OSDs showed good uniformity of mass and content and exhibited an IR profile with good consistency. Fitting a mathematical model to the dissolution data correlated rate parameters and release exponents with tablet porosity. This study illustrates how additive manufacturing via melt extrusion using this MicroFactory not only streamlines the manufacturing process (one-step vs. two-step) but also enables the processing of (brittle) pharmaceutical immediate-release polymers/polymer formulations, improving and facilitating targeted in vitro drug dissolution profiles. Full article

Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure–activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R² = 0.980, Q² = 0.765) and comparative molecular similarity index analysis (CoMSIA, R² = 0.997, Q² = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC₅₀ values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was −93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors. Full article

Cancer is a serious threat to human life and social development and the use of scientific methods for cancer prevention and control is necessary. In this study, HQSAR, CoMFA, CoMSIA and TopomerCoMFA methods are used to establish models of 65 imidazo[4,5-b]pyridine derivatives to explore the quantitative structure-activity relationship between their anticancer activities and molecular conformations. The results show that the cross-validation coefficients q² of HQSAR, CoMFA, CoMSIA and TopomerCoMFA are 0.892, 0.866, 0.877 and 0.905, respectively. The non-cross-validation coefficients r² are 0.948, 0.983, 0.995 and 0.971, respectively. The externally validated complex correlation coefficients r²_pred of external validation are 0.814, 0.829, 0.758 and 0.855, respectively. The PLS analysis verifies that the QSAR models have the highest prediction ability and stability. Based on these statistics, virtual screening based on R group is performed using the ZINC database by the Topomer search technology. Finally, 10 new compounds with higher activity are designed with the screened new fragments. In order to explore the binding modes and targets between ligands and protein receptors, these newly designed compounds are conjugated with macromolecular protein (PDB ID: 1MQ4) by molecular docking technology. Furthermore, to study the nature of the newly designed compound in dynamic states and the stability of the protein-ligand complex, molecular dynamics simulation is carried out for N3, N4, N5 and N7 docked with 1MQ4 protease structure for 50 ns. A free energy landscape is computed to search for the most stable conformation. These results prove the efficient and stability of the newly designed compounds. Finally, ADMET is used to predict the pharmacology and toxicity of the 10 designed drug molecules. Full article

Eicosanoids and other oxylipins represent a superfamily of bioactive lipids involved in the regulation of crucial biological processes such as inflammation, blood clotting or endothelial reactivity. Oxylipins are generated from polyunsaturated fatty acids (PUFAs) through various enzymatic and free-radical-mediated reactions. Interestingly, each metabolic step (PUFA availability, enzyme activity and oxidative stress) can be influenced by diet. Oxylipins could therefore be important mediators of the effects of diet on human health. To provide new insights into the relationships between oxylipins, fatty acids (FAs) and diet, we conducted two independent cohort studies nested in the Polish branch of the PURE international cohort and in the French Nutrinet-Santé cohort, respectively. The selected participants (n = 318) were healthy and fully characterized for their dietary intake. Our first objective was to determine if a healthy diet was associated with a specific oxylipin signature. Our secondary objective was to comprehensively investigate the relationships between diet, FAs and oxylipins. Participants were distributed into two groups according to the quality of their diet (based on the Alternative Healthy Eating Index (AHEI)). Targeted lipidomics was performed to comprehensively quantify plasma oxylipins and FAs. The association between oxylipins, FAs and the quality of the diet was modeled using conditional logistic regression. The relationships between oxylipins, FAs and diet were investigated using an unsupervised multiblock analysis (Multiblock Factorial Analysis (MFA)). We generated a unique database revealing unsuspected associations between diet, FAs and oxylipins. Validation studies are now required to further explore the potential of oxylipins to monitor the health effects of diet. Full article

The regulation of wastewater treatment plants (WWTPs) is a challenge due to their complex biological and chemical characteristics and their accurate mathematical model is generally not accessible because of the limitation of available measurements. To overcome such challenges, in this paper, a novel model-free adaptive nonsingular fast integral terminal sliding mode control (MFA-NFITSMC) is proposed. Firstly, based on the concept of dynamic linearization, a compact format dynamic linearized (CFDL) data model for the WWTP is established. Secondly, a novel fast integral terminal sliding mode surface is proposed to accelerate the convergence of tracking error and a discrete-time MFA-NFITSMC is created using the CFDL model as a basis; then, its stability is proved by theoretical analysis. Finally, the experimental verification is conducted based on the Benchmark Simulation Model No. 1 and the results show that the proposed method has a higher tracking accuracy and stronger robustness than other methods in the control of WWTPs. Full article

Coastal social–ecological systems (SES), particularly in large bays, are critical for fisheries, transportation, and disaster prevention in island and coastal countries. To achieve the sustainability of such bays, public involvement is recently considered inevitable for planning and management, but the increasing complexity of variables and future visions to be considered is one difficulty when trying to include many stakeholders and public opinions. To address this challenge, a free-associative description questionnaire survey was used in this study to extract holistic coastal residents’ future visions for Tokyo Bay, including both positive and negative outcomes. By integrating biterm topic modeling (BTM) and multiple-factor analysis (MFA), this study succeeded to aggregate and visualize the various future visions of Tokyo Bay with enhanced comprehensibility. As one outcome, the linkages and differences between the major topics in the positive and negative future visions were visualized as vectors in a correlation circle. Also, the study found that these two kinds of future vectors are not always polar opposites, but, rather, some of them are interlinked, pointing in the same direction. This highlights the importance of measuring the balance between two kinds of future vectors in consensus-building in order to search for the optimal future direction. Finally, the study discusses the potential of this method as a “Future Compass”, for implementing future-oriented consensus-building toward the sustainability of SES. Full article

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure–activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field Analysis (q² = 0.778, ${\mathrm{R}}_{\mathrm{pred}}^2$ = 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q² = 0.764, ${\mathrm{R}}_{\mathrm{pred}}^2$ = 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the compounds (D1, D4, and Z17) and the template molecule 18x were explored with molecular dynamics simulations, binding free energy calculations by MM/PBSA method as well as the ADME (absorption, distribution, metabolism, and excretion) prediction. The results suggested that D1, D4, and Z17 performed better than template molecule 18x due to the introduction of the amino and hydrophobic groups, especially for the D1 and D4, which will provide guidance for the design of LSD1 inhibitors. Full article

Ligand modification by substituting chemical groups within the binding pocket is a popular strategy for kinase drug development. In this study, a series of pteridin-7(8H)-one derivatives targeting wild-type FMS-like tyrosine kinase-3 (FLT3) and its D835Y mutant (FL3_D835Y) were studied using a combination of molecular modeling techniques, such as docking, molecular dynamics (MD), binding energy calculation, and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies. We determined the protein–ligand binding affinity by employing molecular mechanics Poisson–Boltzmann/generalized Born surface area (MM-PB/GBSA), fast pulling ligand (FPL) simulation, linear interaction energy (LIE), umbrella sampling (US), and free energy perturbation (FEP) scoring functions. The structure–activity relationship (SAR) study was conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), and the results were emphasized as a SAR scheme. In both the CoMFA and CoMSIA models, satisfactory correlation statistics were obtained between the observed and predicted inhibitory activity. The MD and SAR models were co-utilized to design several new compounds, and their inhibitory activities were anticipated using the CoMSIA model. The designed compounds with higher predicted pIC₅₀ values than the most active compound were carried out for binding free energy evaluation to wild-type and mutant receptors using MM-PB/GBSA, LIE, and FEP methods. Full article

The upregulation of phosphoinositol-3-kinase γ (PI3Kγ) is deemed to be positively correlated with tumor-associated-macrophage (TAM)-mediated gastric carcinoma (GC). PI3Kγ suppresses tumor necrosis factor-alpha (TNF-α) and interleukin-12 (IL-12) through activation of the AKT/mTOR pathway, which promotes the immunosuppressant phenotype of TAM. Unlike α and β isoforms, δ and γ isoforms are primarily distributed in leucocytes and macrophages. Dual inhibitors against PI3Kδ and PI3Kγ have been proven to have merits in targeting solid tumors. Furthermore, it has been found that PI3Kδ is activated by cytokines, while PI3Kγ is activated by G-protein-coupled receptors (GPCRs). This facilitates determining the functional difference between these two isoforms. For this goal, selective inhibitors would be immensely helpful. In the current manuscript, we conducted various molecular modeling studies with a series of isoindolin-1-one derivatives as potent PI3Kγ inhibitors by combining molecular docking, molecular dynamics (MD), molecular mechanics, Poisson–Boltzmann/generalized Born surface area (MM-PB/GBSA) binding free energy calculation, and three-dimensional structure–activity relationship (3D-QSAR) study. To evaluate the selectivity of γ isoform over δ, the molecular modeling studies of idelalisib analogs reported as PI3Kδ inhibitors were also investigated. The contour polyhedrons were generated from the comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) around the ligand-bound active site for both isoforms, which could emphasize plausible explanations for the physicochemical factors that affect selective ligand recognition. The binding modalities of the two isoforms using CoMFA and MD models were compared, which suggested some key differences in the molecular interactions with the ligands and could be summarized as three subsites (one affinity subsite near the C-helix and DFG and two hydrophobic subsites). In the context of the structure–activity relationship (SAR), several new compounds were designed using a fragment-substitution strategy with the aim of selectively targeting PI3Kγ. The pIC₅₀ values of the designed compounds were predicted by the 3D-QSAR models, followed by the MM-PB/GBSA binding energy estimation. The overall findings suggest that the designed compounds have the potential to be used as PI3Kγ inhibitors with a higher binding affinity and selectivity. Full article

Overexpression and frequent mutations in FMS-like tyrosine kinase-3 (FLT3) are considered risk factors for severe acute myeloid leukemia (AML). Hyperactive FLT3 induces premature activation of multiple intracellular signaling pathways, resulting in cell proliferation and anti-apoptosis. We conducted the computational modeling studies of 40 pyrimidine-4,6-diamine-based compounds by integrating docking, molecular dynamics, and three-dimensional structure–activity relationship (3D-QSAR). Molecular docking showed that K644, C694, F691, E692, N701, D829, and F830 are critical residues for the binding of ligands at the hydrophobic active site. Molecular dynamics (MD), together with Molecular Mechanics Poison–Boltzmann/Generalized Born Surface Area, i.e., MM-PB(GB)SA, and linear interaction energy (LIE) estimation, provided critical information on the stability and binding affinity of the selected docked compounds. The MD study suggested that the mutation in the gatekeeper residue F691 exhibited a lower binding affinity to the ligand. Although, the mutation in D835 in the activation loop did not exhibit any significant change in the binding energy to the most active compound. We developed the ligand-based comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models. CoMFA (q² = 0.802, r² = 0.983, and $Q_{F3}^2$ = 0.698) and CoMSIA (q² = 0.725, r² = 0.965 and $Q_{F3}^2$ = 0.668) established the structure–activity relationship (SAR) and showed a reasonable external predictive power. The contour maps from the CoMFA and CoMSIA models could explain valuable information about the favorable and unfavorable positions for chemical group substitution, which can increase or decrease the inhibitory activity of the compounds. In addition, we designed 30 novel compounds, and their predicted pIC₅₀ values were assessed with the CoMSIA model, followed by the assessment of their physicochemical properties, bioavailability, and free energy calculation. The overall outcome could provide valuable information for designing and synthesizing more potent FLT3 inhibitors. Full article

The model-free analysis (MFA) was applied to measure the average rate constant (<k>) for pyrene excimer formation (PEF) in a series of pyrene-labeled dendrons referred to as Py_x-G(N), where x (= 2^N) is the number of pyrenyl labels born by a dendron of generation N ranging from 1 to 6. <k> was measured in four different solvents, namely tetrahydrofuran (THF), toluene, N,N-dimethylformamide (DMF), and dimethylsulfoxide (DMSO). <k> was found to increase linearly with increasing local pyrene concentration ([Py]_loc), where [Py]_loc had been determined mathematically for the Py_x-G(N) dendrons. The slope of each straight line changed with the nature of the solvent and represented k_diff, the bimolecular rate constant for PEF. k_diff depended on the solvent viscosity (η) and the probability (p) for PEF upon encounter between an excited and a ground-state pyrene. In a same solvent, k_diff for the Py_x-G(N) dendrons was about 360 ± 30 times smaller than k_diff obtained for ethyl 4-(1-pyrene)butyrate (PyBE), a pyrene model compound similar to the pyrene derivative used to label the dendrons. The massive decrease in k_diff observed for the Py_x-G(N) samples reflected the massive loss in mobility experienced by the pyrenyl labels after being covalently attached onto a macromolecule compared to freely diffusing PyBE. Interestingly, the k_diff values obtained for the Py_x-G(N) dendrons and the PyBE model compound followed similar trends as a function of solvent, indicating that the difference in behavior between the k_diff values obtained in different solvents were merely due to the changes in the η and p values between the solvents. Normalizing the <k> values obtained with the Py_x-G(N) dendrons by the k_diff values obtained for PyBE in the same solvents accounted for changes in η and p, resulting in a master curve upon plotting <k>/(f_diff × k_diff) as a function of [Py]_loc, where f_diff was introduced to account for some pyrene aggregation in the higher generation dendron (Py₆₄-G(6)). This result demonstrates that <k> represents a direct measure of [Py]_loc in pyrene-labeled macromolecules. Full article

Overexpression of lysine specific demethylase 1 (LSD1) has been found in many cancers. New anticancer drugs targeting LSD1 have been designed. The research on irreversible LSD1 inhibitors has entered the clinical stage, while the research on reversible LSD1 inhibitors has progressed slowly so far. In this study, 41 stilbene derivatives were studied as reversible inhibitors by three-dimensional quantitative structure–activity relationship (3D-QSAR). Comparative molecular field analysis (CoMFA ${\mathrm{q}}^2$ = 0.623, ${\mathrm{r}}^2$ = 0.987, ${\mathrm{r}}_{\mathrm{pred}}^2$ = 0.857) and comparative molecular similarity indices analysis (CoMSIA ${\mathrm{q}}^2$ = 0.728, ${\mathrm{r}}^2$ = 0.960, ${\mathrm{r}}_{\mathrm{pred}}^2$ = 0.899) were used to establish the model, and the structure–activity relationship of the compounds was explained by the contour maps. The binding site was predicted by two different kinds of software, and the binding modes of the compounds were further explored. A series of key amino acids Val288, Ser289, Gly314, Thr624, Lys661 were found to play a key role in the activity of the compounds. Molecular dynamics (MD) simulations were carried out for compounds 04, 17, 21, and 35, which had different activities. The reasons for the activity differences were explained by the interaction between compounds and LSD1. The binding free energy was calculated by molecular mechanics generalized Born surface area (MM/GBSA). We hope that this research will provide valuable information for the design of new reversible LSD1 inhibitors in the future. Full article

A series of 7-hydroxy, 8-hydroxy and 7,8-dihydroxy synthetic chromone derivatives was evaluated for their DPPH free radical scavenging activities. A training set of 30 synthetic chromone derivatives was subject to three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using molecular field analysis (MFA). The substitutional requirements for favorable antioxidant activity were investigated and a predictive model that could be used for the design of novel antioxidants was derived. Regression analysis was carried out using genetic partial least squares (G/PLS) method. A highly predictive and statistically significant model was generated. The predictive ability of the developed model was assessed using a test set of 5 compounds (r²_pred = 0.924). The analyzed MFA model demonstrated a good fit, having r² value of 0.868 and crossvalidated coefficient r²_cv value of 0.771. Full article