Free Energy Of Interaction Research Articles

Design of some phthalazine molecules as novel VEGFR-2 target inhibitors through 3D-QSAR modeling, molecular docking and dynamic simulation and pharmacokinetics profiling

AbstractBreast cancer is one of the dominant cause of cancer-related mortality in females, with an incidence of approximately 1.3 million cases annually, necessitating the development of effective therapeutic strategies. In this study, 3D-QSAR models were reported based on Phthalazine derivatives as VEGFR-2 inhibitors. The activities of these derivatives were correlated with the steric (S), electrostatic (E), hydrogen bond acceptor (A), and donor (D), and hydrophobic (H) fields, which served as critical parameters in model development. Statistical studies of these models showed that the best models are; CoMFA_S (Q2 = 0.623, R2 = 0.941), and CoMSIA_E + D (Q2 = 0.615, R2 = 0.977). Based on the insights from the model fields and docking simulation of the template (compound 17), twelve molecules were designed. These novel molecules exhibited stronger potency compared to the template and the standard, Sorafenib. Compound 17A emerged as the most potent, with pIC50 = 5.98, for CoMFA_S and 5.85, for CoMSIA_E + D, and a strong docking affinity of − 97.271 kcal/mol, therefore subjected to a 100-ns MD simulation. Results indicate better interaction and stabilizing potential over Sorafenib, due to the lower RMSD, RMSF, Rg, values and favorable hydrogen bond analyses. These conclusions were validated by Gibbs free energy analysis and MM-GBSA calculations, revealing a more favorable interaction free energy of − 18.48 kcal/mol related to Sorafenib. Furthermore, these designed compounds demonstrated promising pharmacokinetic profiles.

Design, Synthesis, Anti-Cancer, Anti-Inflammatory and In Silico Studies of 3-Substituted-2-Oxindole Derivatives.

This study focuses on the design and synthesis of 3-substituted-2-oxindole derivatives aimed at developing dual-active molecules with anti-cancer and anti-inflammatory properties. The molecules were designed with diverse structural and functional features while adhering to Lipinski, Veber, and Leeson criteria. Physicochemical properties were assessed using SWISSADME to ensure drug-likeness and favourable pharmacokinetics. Multistep synthetic procedures were employed for molecule synthesis. In vitro evaluations confirmed the dual activity of the derivatives, with specific emphasis on the significance of dialkyl aminomethyl substitutions for potency against various cell lines. 4 a exhibited GI50 value 3.00E-05 against MDA-MB-231, 4 b has shown GI50 value 2E-05 against MDA-MB-231, 4 c has shown GI50 value 6E-05 against VERO, 4 d has shown GI50 value 8E-05 each against both the MDA-MB-231 and MCF-7 and 4 e has shown GI50 values 2E-05 and 5E-05 each against both the MCF-7 and VERO. The analysis indicates that compounds 3 c (71.19 %), 3 e (66.84 %), and 3 g (63.04 %) exhibited significant anti-inflammatory activity. Additionally, in silico binding free energy analysis and interaction studies revealed significant correlations between in vitro and computational data, identifying compounds 4 d, 4 e, 3 b, 3 i, and 3 e as promising candidates. Key residues such as Glu917, Cys919, Lys920, Glu850, Lys838, and Asp1046 were found to play critical roles in ligand binding and kinase inhibition, providing valuable insights for designing potent VEGFR2 inhibitors. The Quantum Mechanics-based Independent Gradient Model analysis further highlighted the electronic interaction landscape, showing larger attractive peaks and higher electron density gradients for compounds 4 d and 4 e compared to Sunitinib, suggesting stronger and more diverse attractive forces. These findings support the potential of these compounds for further development and optimization in anticancer drug design.

Developing and Benchmarking Sulfate and Sulfamate Force Field Parameters via Ab Initio Molecular Dynamics Simulations To Accurately Model Glycosaminoglycan Electrostatic Interactions.

Glycosaminoglycans (GAGs) are negatively charged polysaccharides found on cell surfaces, where they regulate transport pathways of foreign molecules toward the cell. The structural and functional diversity of GAGs is largely attributed to varied sulfation patterns along the polymer chains, which makes understanding their molecular recognition mechanisms crucial. Molecular dynamics (MD) simulations, thanks to their unmatched microscopic resolution, have the potential to be a reference tool for exploring the patterns responsible for biologically relevant interactions. However, the capability of molecular dynamics force fields used in biosimulations to accurately capture sulfation-specific interactions is not well established, partly due to the intrinsic properties of GAGs that pose challenges for most experimental techniques. In this work, we evaluate the performance of molecular dynamics force fields for sulfated GAGs by studying ion pairing of Ca2+ to sulfated moieties─N-methylsulfamate and methylsulfate─that resemble N- and O-sulfation found in GAGs, respectively. We tested available nonpolarizable (CHARMM36 and GLYCAM06) and explicitly polarizable (Drude and AMOEBA) force fields, and derived new implicitly polarizable models through charge scaling (prosECCo75 and GLYCAM-ECC75) that are consistent with our developed "charge-scaling" framework. The calcium-sulfamate/sulfate interaction free energy profiles obtained with the tested force fields were compared against reference ab initio molecular dynamics (AIMD) simulations, which serve as a robust alternative to experiments. AIMD simulations indicate that the preferential Ca2+ binding mode to sulfated GAG groups is solvent-shared pairing. Only our scaled-charge models agree satisfactorily with the AIMD data, while all other force fields exhibit poorer agreement, sometimes even qualitatively. Surprisingly, even explicitly polarizable force fields display a notable disagreement with the AIMD data, likely attributed to difficulties in their optimization and possible inherent limitations in depicting high-charge-density ion interactions accurately. Finally, the underperforming force fields lead to unrealistic aggregation of sulfated saccharides, which qualitatively disagrees with our understanding of the soft glycocalyx environment. Our results highlight the importance of accurately treating electronic polarization in MD simulations of sulfated GAGs and caution against over-reliance on currently available models without thorough validation and optimization.

Spiky tubular nanoparticles with low protein corona can realize efficient and non-destructive penetration through endothelial barrier

Upon intravascular applications, i.e., cancer treatment, nanoparticles (NPs) are required to deliver through blood circulation, sustain serum protein interactions, before they penetrate the blood vessels and reach targeted sites for payload drug release. For a delivery process as such, it is elusive and difficult to comprehend the morphological change of NP surface and evaluate associated effects on its targeted delivery. Herein, we used silica NPs with different surface modifications to demonstrate the morphological impact of NPs during the application of the NP-blood protein interaction, vascular endothelial cell penetration, subsequent targeted delivery and photodynamic therapy efficacy, and pursue high drug-load NPs with surface designs. Compared to solid and mesoporous NPs, we found the spiky tubular NPs reserved the NPs' antifouling properties (or shedding of “protein corona”), promoted better endothelial penetration and less destruction in vitro and in vivo. Such effects could be attributed to their spiky surface structures, which can limit the NP-protein interaction area and promote the NP-protein steric hindrance. Further in molecular simulations, we determined that the spiky tubular morphological modification on NPs enhanced the interaction free energy and lowered the amino acids number and the subsequent frequency in contacting with VE-cadherin of vascular endothelia. As a result, the spiky tubular NPs demonstrated its advantages in mitigating damages to VE-cadherin stability and endothelial cell integrity. Exploiting such spiky tubular surface modification, we can improve the NP delivery efficiency and prohibit the leakiness of vascular endothelia, helping address challenges faced by tumor migration in nanomedicine applications for cancer therapy.

Transcending Lifshitz Theory: Reliable Prediction of Adhesion Forces between Hydrocarbon Surfaces in Condensed Phases Using Molecular Contact Thermodynamics.

Lifshitz theory is widely used to calculate interfacial interaction energies and underpins established approaches to the interpretation of measurement data from experimental methods including the surface forces apparatus and the atomic force microscope. However, a significant limitation of Lifshitz theory is that it uses the bulk dielectric properties of the medium to predict the work of adhesion. Here, we demonstrate that a different approach, in which the interactions between molecules at surfaces and in the medium are described by a set of surface site interaction points (SSIPs), yields interaction free energies that are correlated better with experimentally determined values. The work of adhesion W(Lifshitz) between hydrocarbon surfaces was calculated in 260 liquids using Lifshitz theory and compared with interaction free energies ΔΔG calculated using the SSIP model. The predictions of these models diverge in significant ways. In particular, ΔΔG values for hydrocarbon surfaces are typically small and vary little, but in contrast, W(Lifshitz) values span 4 orders of magnitude. Moreover, the SSIP model yields significantly different ΔΔG values in some liquids for which Lifshitz theory predicts similar values of W(Lifshitz). These divergent predictions were tested using atomic force microscopy. Experimentally determined works of adhesion were closer to the values predicted using the SSIP model than Lifshitz theory. In mixtures of methanol and benzyl alcohol, even greater differences were found in the interaction energies calculated using the two models: the value of ΔΔG calculated using the SSIP model declines smoothly as the benzyl alcohol concentration increases, and values are well correlated with experimental data; however, W(Lifshitz) decreases to a minimum and then increases, reaching a larger value for benzyl alcohol than for methanol. We conclude that the SSIP model provides more reliable estimates of the work of adhesion than Lifshitz theory.

Carbon Nanotube Loading Strategies for Peptide Drugs: Insights from Molecular Dynamics Simulations.

Carbon nanotubes (CNTs) can be regarded as a potential platform for transmembrane drug delivery as many experimental works have demonstrated their capability to effectively transport bioactive molecules into living cells. Within this framework, the loading of a peptide drug onto either the interior or exterior of CNTs has gained considerable interest. This study aims to conduct a comprehensive comparison of these two loading methods. To this end, we performed molecular dynamics simulations and the umbrella sampling technique to investigate the interaction energy, conformational changes, and free energy changes of a model peptide drug containing α-helical structure interacting with the inner or outer walls of a 14.7-nm-long (20,20) CNT. Our finding reveals that, for a tube of such dimensions, it is thermodynamically more favorable for the peptide to be loaded onto the inner tube wall than the outer tube wall, primarily due to a larger free energy change for the former strategy. Conversely, unloading the drug from the tube interior poses greater challenges. Moreover, the tube's curvature plays an essential role in influencing the conformation of the adsorbed peptide. Despite the relatively weaker van der Waals interaction between the CNT exterior and the peptide, loading the peptide onto the exterior may induce significant conformational changes, particularly affecting the peptide's α-helix structure. In contrast, loading of the peptide on the CNT interior could maintain most of the α-helical content. CNTs do not typically attract specific peptide residues, with adsorbed groups primarily determined by the peptide's configurations and orientations. Finally, we offer a guideline for selecting an optimal loading strategy for CNT-based drug delivery.

Adsorption of Glycine on TiO2 in Water from On-the-fly Free-Energy Calculations and In Situ Electrochemical Impedance Spectroscopy.

We report here an experimental-computational study of hydrated TiO2 anatase nanoparticles interacting with glycine, where we obtain quantitative agreement of the measured adsorption free energies. Ab initio simulations are performed within the tight binding and density functional theory in combination with enhanced free-energy sampling techniques, which exploit the thermodynamic integration of the unbiased mean forces collected on-the-fly along the molecular dynamics trajectories. The experiments adopt a new and efficient setup for electrochemical impedance spectroscopy measurements based on portable screen-printed gold electrodes, which allows fast and in situ signal assessment. The measured adsorption free energy is -30 kJ/mol (both from experiment and calculation), with preferential interaction of the charged NH3+ group which strongly adsorbs on the TiO2 bridging oxygens. This highlights the importance of the terminal amino groups in the adsorption mechanism of amino acids on hydrated metal oxides. The excellent agreement between computation and experiment for this amino acid opens the doors to the exploration of the interaction free energies for other moderately complex bionano systems.

Photoluminescence-based biosensor for the detection of antibodies against SARS-CoV-2 virus proteins by ZnO tetrapod structure integrated within microfluidic system

This paper reports on development of an optical biosensor for the detection of antibodies against SARS-CoV-2 virus proteins in blood serum. ZnO nanotetrapods with high surface area and stable room temperature photoluminescence (PL) were selected as transducers. Structure and optical properties of the ZnO tetrapods have been studied by XRD, SEM and Raman spectroscopy. Crystallinity, dimensions and emission peaks of the ZnO tetrapods were determined. The ZnO tetrapods were fixed on glass chip. Silanization of ZnO tetrapods surface resulted in forming of functional surface groups suitable for the immobilization of bioselective layer. Two types of recombinant proteins (rS and rN) have been used to form bioselective layer on the surface of the ZnO tetrapods. Flow through microfluidic system, integrated with optical system, has been used for the determination of antibodies against SARS-CoV-2 virus proteins present in blood samples. The SARS-CoV-2 probes, prepared in PBS solution, have been injected into the measurement chamber with a constant pumping speed. Steady-state photoluminescence spectra and photoluminescence kinetics have been studied before and after injection of the probes. The biosensor signal has been tested to anti-SARS-CoV-2 antibodies in the range of 0.001 nM–1 nM. Control measurements have been performed with blood serum of healthy person. ZnO-SARS-CoV-2-rS and ZnO-SARS-CoV-2-rN biosensors showed high stability and sensitivity to anti-SARS-CoV-2 antibodies in the range of 0.025–0.5 nM (LOD 0.01 nM) and 0.3–1 nM (LOD 0.3 nM), respectively. Gibbs free energy of interaction between ZnO/SARS-CoV-2-rS and ZnO/SARS-CoV-2-rN bioselective layers with anti-SARS-CoV-2 antibodies showed −35.5 and −21.4 kJ/mol, respectively. Average detection time of biosensor integrated within microfluidic system was 15–20 min. The detection time and pumping speed (50 μL/min) were optimized to make detection faster. The developed system and ZnO-SARS-CoV-2-rS nanostructures have good potential for detection of anti-SARS-CoV-2 antibodies from patient's probes.

Theoretical study on the influence of three different surfactants on the binding of laccase with bisphenol A

Laccase catalyzes the formation of phenoxyl radicals as an intermediate in Bisphenol A (BPA) degradation, and certain surfactants can affect the effectiveness of laccase in removing BPA from various effluents, yet the specific molecular details remain unclear. In this study, based on laccase and BPA complex, three surfactants, cetyltrimethylammonium bromide (CTAB), sodium dodecylbenzene sulfonate (SDBS), and TritonX-100 (TX-100), were introduced to construct four systems. We applied MD simulation along with MM-PBSA method to investigate the effects of different surfactants on the binding of laccase with BPA. During the MD simulations, these three surfactants enveloped the enzyme surface to varying degrees, causing the solvent to separate from parts of the laccase surface. The addition of CTAB and SDBS suppressed BPA degradation mainly by influencing the polar solvation free energy and van der Waals (vdW) interactions between laccase and BPA. In contrast, TX-100 promoted the degradation of BPA by reducing polar solvation free energy. This explains why in the laccase-BPA complex system the addition of a certain concentration of TX-100 resulted in a higher degradation rate compared to CTAB or SDBS. Our work clarifies the molecular mechanisms of the interaction between laccase and BPA under the influence of CTAB, SDBS, and TX-100 surfactants, and provides some guidance for laccase degradation of BPA.

Investigating spectroscopic properties, biological effects, and molecular docking studies of synthesized Schiff base metal complexes

In this current investigation, we have accomplished the synthesis of a Schiff base ligand termed (E)-4-methyl-N′-(2,4,5-trimethoxybenzylidene)benzohydrazide (HL) through a reversible condensation reaction, which engaged a carbonyl compound and a primary amine. This synthesized Schiff base ligand, HL, served as the foundation for the preparation of two metal complexes, namely, M1L (Cu complex) and M2L (La complex). To characterize these compounds, we employed various analytical techniques, including thermogravimetric studies, elemental analysis, powder X-ray diffraction, FT-IR spectroscopy and 1H NMR. The examination of powder X-ray diffraction data provided valuable insights into the crystalline structures of the Cu and La complexes. These shifts are indicative of structural changes in the complexes. Our electronic spectrum analysis revealed the pivotal involvement of the ligand in promoting charge transfer processes, substantiated by an increased concentration of charge transfer transitions observed when the ligand was present. Additionally, we evaluated the antibacterial efficacy of the Schiff base ligand HL and its metal complexes (Cu, La) against a spectrum of bacteria, encompassing both gram-positive (Bacillus subtilis, Enterococcus faecalis) and gram-negative (Escherichia coli) strains. In the current investigation, we utilized molecular docking techniques to explore the interactions between the synthesized HL and its M1L and M2L complexes with protein receptor molecules. These results highlighted the favorable binding energies and stable interactions of these compounds with the protein receptor, M1L displayed notably more stable interactions and lower binding energy compared to M2L. This suggests that M1L may have a stronger potential impact on the free binding energy and molecular interactions.

Mapping the transporter-substrate interactions of the Trypanosoma cruzi NB1 nucleobase transporter reveals the basis for its high affinity and selectivity for hypoxanthine and guanine and lack of nucleoside uptake

Trypanosoma cruzi is a protozoan parasite and the etiological agent of Chagas disease, a debilitating and sometimes fatal disease that continues to spread to new areas. Yet, Chagas disease is still only treated with two related nitro compounds that are insufficiently effective and cause severe side effects. Nucleotide metabolism is one of the known vulnerabilities of T. cruzi, as they are auxotrophic for purines, and nucleoside analogues have been shown to have genuine promise against this parasite in vitro and in vivo. Since purine antimetabolites require efficient uptake through transporters, we here report a detailed characterisation of the T. cruzi NB1 nucleobase transporter with the aim of elucidating the interactions between TcrNB1 and its substrates and finding the positions that can be altered in the design of novel antimetabolites without losing transportability. Systematically determining the inhibition constants (Ki) of purine analogues for TcrNB1 yielded their Gibbs free energy of interaction, ΔG0. Pairwise comparisons of substrate (hypoxanthine, guanine, adenine) and analogues allowed us to determine that optimal binding affinity by TcrNB1 requires interactions with all four nitrogen residues of the purine ring, with N1 and N9, in protonation state, functioning as presumed hydrogen bond donors and unprotonated N3 and N7 as hydrogen bond acceptors. This is the same interaction pattern as we previously described for the main nucleobase transporters of Trypanosoma brucei spp. and Leishmania major and makes it the first of the ENT-family genes that is functionally as well as genetically conserved between the three main kinetoplast pathogens.

In Silico Investigations on the Synergistic Binding Mechanism of Functional Compounds with Beta-Lactoglobulin.

Piceatannol (PIC) and epigallocatechin gallate (EGCG) are polyphenolic compounds with applications in the treatment of various diseases such as cancer, but their stability is poor. β-lactoglobulin (β-LG) is a natural carrier that provides a protective effect to small molecule compounds and thus improves their stability. To elucidate the mechanism of action of EGCG, PIC, and palmitate (PLM) in binding to β-LG individually and jointly, this study applied molecular docking and molecular dynamics simulations combined with in-depth analyses including noncovalent interaction (NCI) and binding free energy to investigate the binding characteristics between β-LG and compounds of PIC, EGCG, and PLM. Simulations on the binary complexes of β-LG + PIC, β-LG + EGCG, and β-LG + PLM and ternary complexes of (β-LG + PLM) + PIC, (β-LG + PLM) + EGCG, β-LG + PIC) + EGCG, and (β-LG + EGCG) + PIC were performed for comparison and characterizing the interactions between binding compounds. The results demonstrated that the co-bound PIC and EGCG showed non-beneficial effects on each other. However, the centrally located PLM was revealed to be able to adjust the binding conformation of PIC, which led to the increase in binding affinity with β-LG, thus showing a synergistic effect on the co-bound PIC. The current study of β-LG co-encapsulated PLM and PIC provides a theoretical basis and research suggestions for improving the stability of polyphenols.

Natural Compound Dioscin Targeting Multiple Cancer Pathways through its High Affinity Binding to B Cell Lymphoma-2.

The study aimed to explore the crucial genes involved in cancer-related biological processes, including EMT, autophagy, apoptosis, anoikis, and metastasis. It also sought to identify common genes among the pathways linked to these biological processes, determine the level of Bcl-2 expression in various types of cancers, and find a potent inhibitor of Bcl-2 among natural compounds. Common genes involved in the pathways related to EMT, autophagy, apoptosis, anoikis, and metastasis were explored, and the level of the most frequently overexpressed gene that was Bcl-2, in various types of cancers was analyzed by gene expression analysis. A set of 102 natural compounds was sorted according to their docking scores using molecular docking and filtering. The top-ranked molecule was chosen for additional molecular dynamics (MD) simulation for 100 ns. Differential gene expression analysis was performed for Dioscin using GEO2R. The study identified four common genes, Bcl-2, Bax, BIRC3, and CHUK, among the pathways linked to EMT, autophagy, apoptosis, anoikis, and metastasis. Bcl-2 was highly overexpressed in many cancers, including Acute Myeloid Leukemia, Diffuse large B cell lymphoma, and Thymoma. The Dioscin structure in the Bcl-2 binding site received the highest docking score and the most relevant interactions. Dioscin's determined binding free energy by MM/GBSA was -52.21 kcal/mol, while the same calculated by MM/PBSA was -9.18 kcal/mol. A p-value of less than 0.05 was used to determine the statistical significance of the analysis performed using GEO2R. It was observed that Dioscin downregulates Bcl-2, BIRC3, and CHUK and upregulates the pro-apoptotic protein Bax. The study concluded that Dioscin has the potential to act as a protein inhibitor, with a noteworthy value of binding free energy and relevant interactions with the Bcl-2 binding site. Dioscin might be a good alternative for targeting multiple cancer pathways through a single target.

Correlation of Experimental and Calculated Inhibition Constants of Protease Inhibitor Complexes.

Predicting the potency of inhibitors is key to in silico screening of promising synthetic or natural compounds. Here we describe a predictive workflow that provides calculated inhibitory values, which concord well with empirical data. Calculations of the free interaction energy ΔG with the YASARA plugin FoldX were used to derive inhibition constants Ki from PDB coordinates of protease-inhibitor complexes. At the same time, corresponding KD values were obtained from the PRODIGY server. These results correlated well with the experimental values, particularly for serine proteases. In addition, analyses were performed for inhibitory complexes of cysteine and aspartic proteases, as well as of metalloproteases, whereby the PRODIGY data appeared to be more consistent. Based on our analyses, we calculated theoretical Ki values for trypsin with sunflower trypsin inhibitor (SFTI-1) variants, which yielded the more rigid Pro14 variant, with probably higher potency than the wild-type inhibitor. Moreover, a hirudin variant with an Arg1 and Trp3 is a promising basis for novel thrombin inhibitors with high potency. Further examples from antibody interaction and a cancer-related effector-receptor system demonstrate that our approach is applicable to protein interaction studies beyond the protease field.

Corrosion-induced changes in surface properties and roughness of orthodontic wires

This study aimed to investigate the surface free energy and surface roughness (SR) of metallic alloys under the influence of acid solutions. The experiment involved the use of 270 rectangular wire samples measuring 0.019 × 0.025-in. These samples were sourced from 3 different commercial brands: Dentsply GAC, American Orthodontics, and Orthoclassic. This invitro study categorized the samples into 3 groups based on the solutions employed: deionized water, citric acid, and phosphoric acid. Each group consisted of 90 samples, with 30 samples representing each type of alloy-stainless steel, nickel-titanium, and titanium molybdenum alloy (TMA). The wire segments were immersed in their respective solutions for 72 hours at a controlled temperature of 37°C, with continuous orbital agitation at 130 rpm. After the immersion period, the study analyzed both surface free energy and SR. The mean values obtained were subjected to an analysis of variance at a significance level of 5%. All alloys displayed hydrophobic behavior, as indicated by interaction free energy values<0. In acidic environments (phosphoric acid and citric acid), significant differences were observed among different brands and alloys, affecting surface energy and interaction free energy. Variations in SR among metallic alloys included steel with the lowest SR variations, followed by nickel-titanium and TMA. Notably, the TMA alloy stood out with significantly higher surface energy compared with that of the other alloys (P<0.001). In this study, all examined alloys demonstrated a hydrophobic nature, suggesting a limited attraction to water. Notably, TMA exhibited the least hydrophobic behavior among the alloys studied. However, when exposed to citric acid, TMA displayed the most substantial alterations in its surface properties. These results underscored the significance of accounting for the distinctive properties of each alloy and their responses to diverse challenges, such as exposure to acidic solutions, during the selection of orthodontic wires for orthodontics treatment.

Mixing temperature optimization and modification mechanism of medical masks modified asphalt: Insights from computational chemistry

Masks modified asphalt (MMA) offers a solution to pollution caused by discarded medical masks. Mixing temperature plays a crucial role in storage stability and even rheological performance of MMA. Traditional selection method overly relies on trial-and-error experiment, neglecting the convenience offered by computational chemistry. Furthermore, previous literature lacks precise elucidation of MMA’s physical modification mechanism, especially concerning the binding mode and energy composition. To address these issues, the optimal mixing temperature for MMA was recommended based on molecular dynamics. The rationality of recommended temperature was validated through laboratory tests, simultaneously investigating the impact of heating time. Fluorescence microscopy and multi-band spectroscopy were employed to acquire the microstructure. Binding modes in MMA were determined using binding sites exploration, evaluating the energy composition of each binding mode through quantum chemistry. The interaction mechanism was explained based on surface properties of isolated molecules. Results indicated that 170℃ was the recommended optimal mixing temperature derived from mixing free energy and Flory-Huggins interaction parameter. The fluctuations in softening point difference (ΔTR&B) and separation ratio (RS) concurrently tended towards stability, thereby validating the reliability of recommended temperature. Moreover, even after 72 h heating, MMA prepared at recommended temperature remained within a reasonable range concerning ΔTR&B, RS, and microscopic structure. Perpendicular, parallel, toroidal, and spherical modes emerged in MMA. Perpendicular and parallel modes exhibited the highest binding energies, while circular mode demonstrated the lowest. Binding energy is primarily governed by van der Waals interaction, attributed to the dominance of dispersion term on MMA’s molecular surface. Besides, due to the presence of polycyclic aromatic hydrocarbons in asphalt molecules, electrostatic interaction contributed to specific molecular bindings.

Enantioselective Glutamic Acid Discrimination and Nanobiological Imaging by Chiral Fluorescent Silicon Nanoparticles.

Enantioselective discrimination of chiral molecules is essential in chemistry, biology, and medical science due to the configuration-dependent activities of enantiomers. Therefore, identifying a specific amino acid and distinguishing it from its enantiomer by using nanomaterials with outstanding performance are of great significance. Herein, blue- and green-emitting chiral silicon nanoparticles named bSiNPs and gSiNPs, respectively, with excellent water solubility, salt resistance, pH stability, photobleaching resistance, biocompatibility, and ability to promote soybean germination, were fabricated in a facile one-step method. Especially, chiral gSiNPs presented excellent fluorescence recognition ability for glutamic acid enantiomers within 1 min, and the enantiomeric recognition difference factor was as high as 9.0. The mechanism for enantiomeric fluorescence recognition was systematically explored by combining the fluorescence spectra with density functional theory (DFT) calculation. Presumably, the different Gibbs free energy and hydrogen-bonding interaction of the chiral recognition module with glutamic acid enantiomers mainly contributed to the difference in the fluorescence signals. Most noteworthy was the fact that the chiral gSiNPs can showcase not only the ability to recognize l- and d-glutamic acids in living cells but also the test strips fabricated by soaking gSiNPs can be applied for d-glutamic acid visual detection. As a result, this study provided insights into the design of multifunctional chiral sensing nanoplatforms for enantiomeric detection and other applications.

Alchemical approach performance in calculating the ligand-binding free energy.

Alchemical binding free energy calculations are one of the most accurate methods for estimating ligand-binding affinity. Assessing the accuracy of the approach over protein targets is one of the most interesting issues. The free energy difference of binding between a protein and a ligand was calculated via the alchemical approach. The alchemical approach exhibits satisfactory accuracy over four targets, including AmpC beta-lactamase (AmpC); glutamate receptor, ionotropic kainate 1 (GluK1); heat shock protein 90 (Hsp90); and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). In particular, the correlation coefficients between calculated binding free energies and the respective experiments over four targets range from 0.56 to 0.86. The affinity computed via free energy perturbation (FEP) simulations is overestimated over the experimental value. Particularly, the electrostatic interaction free energy rules the binding process of ligands to AmpC and GluK1. However, the van der Waals (vdW) interaction free energy plays an important role in the ligand-binding processes of HSP90 and SARS-CoV-2 Mpro. The obtained results associate with the hydrophilic or hydrophobic properties of the ligands. This observation may enhance computer-aided drug design.

Wave mechanics in an ionic liquid mixture.

Experimental measurements of interactions in ionic liquids and concentrated electrolytes over the past decade or so have revealed simultaneous monotonic and oscillatory decay modes. These observations have been hard to interpret using classical theories, which typically allow for just one electrostatic decay mode in electrolytes. Meanwhile, substantial progress in the theoretical description of dielectric response and ion correlations in electrolytes has illuminated the deep connection between density and charge correlations and the multiplicity of decay modes characterising a liquid electrolyte. The challenge in front of us is to build connections between the theoretical expressions for a pair of correlation functions and the directly measured free energy of interaction between macroscopic surfaces in experiments. Towards this aim, we here present measurements and analysis of the interactions between macroscopic bodies across a fluid mixture of two ionic liquids of widely diverging ionic size. The measured oscillatory interaction forces in the liquid mixtures are significantly more complex than for either of the pure ionic liquids, but can be fitted to a superposition of two oscillatory and one monotonic mode with parameters matching those of the pure liquids. We discuss this empirical finding, which hints at a kind of wave mechanics for interactions in liquid matter.

MOLECULAR INSIGHTS INTO PROPOXAZEPAM INTERACTION WITH TRPV1 RECEPTORS: A DOCKING ANALYSIS

Problem. Pain therapy has remained conceptually stagnant since the opioid crisis, which highlighted the dangers of treating pain with opioids. TRPV1 receptors and their ligands have emerged as promising targets for the management of various pain conditions, including inflammatory and neuropathic pain. Further investigation into the activation and desensitization mechanisms of TRPV1 receptors, as well as the exploration of novel ligands with enhanced selectivity and efficacy, holds the potential to alleviate the burden of chronic pain. Aim. The study of interactions of ligands with the TRPV1 receptor by molecular docking and analysis of components of these interactions. Methods. In order to study the binding energy of the TRPV1 receptor with the researched compounds 8GFA – Cryo-EM structure of human TRPV1 in complex with the analgesic drug SB-366791 was utilized. The docking and QSAR prediction were carried out with propoxazepam, its possible metabolite 3-hydroxopropoxazepam, diazepam, oxazepam, SB-366791, RTX, capsazepin, capsaicin. The docking and QSAR build model using the Maestro Schrödinger Suite. The main results. Propoxazepam has the necessary pharmacophoric features to bind with TRPV1 recepor: region A-benzene ring; region B – the amide group (NH-C=O); region C – alkoxy group. The docking score of propoxazepam (-7.30 kcal/mol) indicates a stronger interaction with the TRPV1 receptor compared to oxazepam (-6.82 kcal/mol), 3-hydroxopropoxazepam (-6.49 kcal/mol), and capsazepin (-6.39 kcal/mol). When considering the increase in the free energy of interactions, the ligands can be ranked as follows: SB-366791 &gt; Capsaicin &gt; RTX &gt; Capsazepin &gt; Propoxazepam &gt; Diazepam &gt; 3-hydroxopropoxazepam &gt; Oxazepam. Propoxazepam establishes two hydrogen bonds: one involving the NH group of the amide (resulting in a hydrogen bond interaction with the linker-neck) and THR550 of the protein, and another between oxygen of the alkoxy group (hydrophobic tail) and TYR511 of the TRPV1 receptor. Ligands with confirmed effects on the TRPV1 receptor also engage in interactions with the protein by forming hydrogen bonds with the same amino acids as the benzodiazepines, namely THR550 and TYR511. Propoxazepam is predicted to have relatively low potency or affinity for TRPV1 (predicted pIC50 value of –1.115), but this value is higher than other ligands. Conclusions. As propoxazepam has the necessary pharmacophoric features of the pharmacophore model of TRPV1 ligands, it could theoretically bind with this receptor. Propoxazepam creates hydrogen bond with TYR511 of the TRPV1 receptor as referent ligand SB-366791. Propoxazepam exhibits one of the largest contributions of hydrogen bonds in the energy of interaction with the receptor. According to QSAR modelling, all studied compounds (3-hydroxopropoxazepam, diazepam, oxazepam, propoxazepam) have low pIC50 values, which could indicate a relatively low potency or affinity for TRPV1. But propoxazepam has the highest predicted pIC50, it means that the model predicts it to be the most potent among the compounds.