Molecular Modeling Calculations Research Articles

Copper(II) Complexes with Isomeric Morpholine-Substituted 2-Formylpyridine Thiosemicarbazone Hybrids as Potential Anticancer Drugs Inhibiting Both Ribonucleotide Reductase and Tubulin Polymerization: The Morpholine Position Matters.

The development of copper(II) thiosemicarbazone complexes as potential anticancer agents, possessing dual functionality as inhibitors of R2 ribonucleotide reductase (RNR) and tubulin polymerization by binding at the colchicine site, presents a promising avenue for enhancing therapeutic effectiveness. Herein, we describe the syntheses and physicochemical characterization of four isomeric proligands H2L3-H2L6, with the methylmorpholine substituent at pertinent positions of the pyridine ring, along with their corresponding Cu(II) complexes 3-6. Evidently, the position of the morpholine moiety and the copper(II) complex formation have marked effects on the in vitro antiproliferative activity in human uterine sarcoma MES-SA cells and the multidrug-resistant derivative MES-SA/Dx5 cells. Activity correlated strongly with quenching of the tyrosyl radical (Y•) of mouse R2 RNR protein, inhibition of RNR activity in the cancer cells, and inhibition of tubulin polymerization. Insights into the mechanism of antiproliferative activity, supported by experimental results and molecular modeling calculations, are presented.

Photo‐Responsive TiO2‐Gold Nanoparticle‐Polymer Nanohybrid Exhibits Photothermal, Thermo‐Release, and Photocatalytic Effects

The development of multi‐responsive nanohybrid systems that combine photothermia, thermo‐responsive effects and photocatalysis is a challenging topic in the research of multifunctional materials with a large field of applications. Here, we report the first example of a three‐components light‐responsive nanosystem consisting of titania, gold nanoparticles and poly‐N‐isopropylacrylamide (TiO2‐Au‐PNM). The hybrid nanostructure exhibited photothermal conversion effect upon green‐light excitation and capacity to entrap methylene blue and curcumin selected as cargo models. The formation of the nanohybrid―cargo adducts, the photothermal‐controlled cargo release triggered by green‐light irradiation (532 nm) and mediated by lower critical solution temperature (LCST), as well as the photocatalytic effect prompted by UV‐light excitation (300 nm) were demonstrated by spectroscopic techniques. The mechanism involved in the interaction of the polymeric component with the cargos was investigated by molecular modelling calculations.

Effect of support type on the characteristics of polybutene polymers from C4 monomers employing supported ionic liquid/AlCl3 initiating systems

In order to assess the effect of support type on the characteristics of polybutene polymers, cyclohexyl imidazolium chloride ionic liquid was grafted onto the surface of various supports including boehmite, halloysite, palygorskite, and kaolinite. The furnished supported ionic liquids were employed alongside AlCl3/ethanol as initiating systems to polymerize C4 monomers, resulting in polybutene polymers. Overall, XRD, FTIR, TGA, SEM, EDS, and Elemental Mapping Analyses convinced the successful homogenous grafting of ionic liquid onto the surface of subjected supports. To obtain precious and essential information about molecular weight, dispersity, and microstructure of polymers, GPC, 1H NMR, and 13C NMR analyses were conducted. Among the four initiating systems, kaolinite supported ionic liquid demonstrated the most satisfying results, Yield = 88.2 %, Mn= 18104 g mol−1, Ð = 1.83, exo= 6.1 % and isobutylene content of 92.5 %. Hence, this supported ionic liquid was fully characterized via SEM, EDX, Elemental Mapping, XRD, FT IR and TGA analyses. To get deeper insight about the type and quantity of molecular interactions in the kaolinite supported ionic liquid, molecular modeling calculation was also considered. Beside efficiently balancing polymerization condition, implementing the AlCl3/ionic liquid initiating system promotes a more environmentally friendly polymerization approach by halving the amount of hazardous AlCl3 compared to the blank system including neat AlCl3 as the single co-initiator.

Computational and experimental approaches into molecular structure mechanism of ZQV coal and the COx gas releases during pyrolysis

Understanding the structural features of coal and its reactive behaviors in thermal processing is the fundamental to achieve high-efficiency utilization of coal. However, the molecular structural features and the evolution characteristics at atomic scales in thermal processing remain unclear in the microscopic views, particularly for the low-rank coals, which usually exhibits high oxygen content with a variety of oxygen-containing organic functional groups and gets lots of CO/CO2 release during pyrolysis. This research provides a comprehensive analysis of the ZaoQuan vitrinite (ZQV) bituminous coal's structural attributes and its pyrolysis-induced reactivity, which is crucial for optimizing the thermal conversion of low-rank coals. The structural parameters characteristics and molecular structures of ZQV have been revealed based on series of materials characterizations and molecular modeling calculations. The single molecular description of ZQV was conceptualized to be C209H132O41N2 under the average molecular approximation, and the particle models with size about 10 nm was also been obtained. Based on the built molecular models, reactive force field molecular dynamics (ReaxFF MD) simulations then provided insights into the dynamic behavior of molecular structures under pyrolysis conditions. Experimental validation corroborates the computational predictions, revealing a strong coherence between observed gas products and those derived from simulation data. Crucially, this study vividly captures the dynamic migration patterns of oxygen-containing groups during coal's thermal decomposition, thus contributing to the understanding of gasification processes. The release mechanisms for CO and CO2 are systematically dissected, proposing three and two distinct pathways respectively. These findings not only consolidate the molecular narrative of coal's structure and pyrolysis reactivity but also serve as a reliable foundation for interpreting the COx evolution of low-rank coals. Our integrated approach propels the scientific comprehension of coal pyrolysis and is anticipated to inform the development of more effective coal utilization pathways and thermal treatment technologies.

Antioxidant, antibacterial, and molecular docking of methyl ferulate and oleic acid produced by Aspergillus pseudodeflectus AUMC 15761 utilizing wheat bran

Secondary metabolites (SMs) are the primary source of therapeutics and lead chemicals in medicine. They have been especially important in the creation of effective cures for conditions such as cancer, malaria, bacterial and fungal infections, neurological and cardiovascular problems, and autoimmune illnesses. In the present study, Aspergillus pseudodeflectus AUMC 15761 was demonstrated to use wheat bran in solid state fermentation (SSF) at optimum conditions (pH 7.0 at 30 °C after 10 days of incubation and using sodium nitrate as a nitrogen source) to produce methyl ferulate and oleic acid with significant antioxidant and antibacterial properties. Gas chromatography-mass spectrometry (GC–MS) analysis of the crude methanol extract revealed eleven peaks that indicated the most common chemical components. Purification of methyl ferulate and oleic acid was carried out by column chromatography, and both compounds were identified by in-depth spectroscopic analysis, including 1D and 2D NMR and HR-ESI–MS. DPPH activity increased as the sample concentration increased. IC50 values of both compounds obtained were 73.213 ± 11.20 and 104.178 ± 9.53 µM, respectively. Also, the MIC value for methyl ferulate against Bacillus subtilis and Staphylococcus aureus was 0.31 mg/mL, while the corresponding MIC values for oleic acid were 1.25 mg/mL and 0.62 mg/mL for both bacterial strains, respectively. Molecular modeling calculations were carried out to reveal the binding mode of methyl ferulate and oleic acid within the binding site of the crucial proteins of Staphylococcus aureus. The docking results were found to be well correlated with the experimental data.

Binding of Acetylated Lysine by Using a Water Soluble Aryl Extended Calix[4]pyrrole.

Post-translational modifications of lysine in histones, as methylation and acetylation, have well established functions in epigenetics and are emerging as important actors in broader biological regulation. Currently, the detection of acetylated lysine (Kac) in water solution as free amino acid or protein residue remains challenging. Acetylated lysine is a neutral amino acid, and the lack of ion-dipole interactions causes the decrease in binding affinity displayed by synthetic molecular receptors with respect to the other lysine modifications. Here, we report molecular modeling calculations and 1H NMR experiments to investigate the binding properties of two different calix[4]pyrrole receptors towards Kac. Computational analyses reveal that tetra-aryl-extended calix[4]pyrrole (1) preferentially binds the cis-Kac conformer over the trans one due to steric considerations and more favorable interactions. Experimental 1H NMR titration experiments confirm the formation of a 1 : 1 complex between receptor 1 and cis-Kac, with a Ka exceeding 103 M-1. Conversely, the super-aryl-extended calix[4]pyrrole 2 is less efficient in binding Kac, due to unfavorable solvation/desolvation effects, as proven by 1H NMR experiments. Moreover, receptor 1 showed a higher affinity for Kac over other lysine modifications, such as methylated lysines.

Three-Dimensional Hydrogen-Bonded Porous Metal-Organic Framework for Natural Gas Separation with High Selectivity.

A 3D hydrogen-bonded metal-organic framework, [Cu(apc)2]n (TJU-Dan-5, Hapc = 2-aminopyrimidine-5-carboxylic acid), was synthesized via a solvothermal reaction. The activated TJU-Dan-5 with permanent porosity exhibits a moderate uptake of 1.52 wt% of hydrogen gas at 77 K. The appropriate BET surface areas and decoration of the internal polar pore surfaces with groups that form extensive hydrogen bonds offer a more favorable environment for selective C2H6 adsorption, with a predicted selectivity for C2H6/CH4 of around 101 in C2H6/CH4 (5:95, v/v) mixtures at 273 K under 100 kPa. The molecular model calculation demonstrates a C-H···π interaction and a van der Waals host-guest interaction of C2H6 with the pore walls. This work provides a strategy for the construction of 3D hydrogen-bonded MOFs, which may have great potential in the purification of natural gas.

γ-Cyclodextrins as Supramolecular Reactors for the Three-component Aza-Darzens Reaction in Water.

In recent decades, many efforts have been devoted to studying reactions catalyzed in nanoconfined spaces. The most impressive aspect of catalysis in nanoconfined spaces is that the reactivity of the molecules can be smartly driven to disobey classical behavior. A green and efficient three-component aza-Darzens (TCAD) reaction using a catalytic amount of γ-cyclodextrins (CDs) in water has been developed to synthesize N-phenylaziridines. CDs effectively performed this reaction in an environmentally friendly setting, achieving good yields. The same reaction was then performed using polymeric γ-CD such as a γ-cyclodextrin polymer crosslinked (GCDPC) with epichlorohydrin, a sponge-like macroporous γ-cyclodextrin-based cryogel (GCDC), and a γ-cyclodextrin-based hydrogel (GCDH). The homogeneous and heterogeneous catalyst recovery was then studied, and it was proved to be easily recycled several times without relevant activity loss. Water, as a unique and eco-friendly reaction medium, has been utilized for the first time, to the best of our knowledge, in this reaction. The inclusion of the reagents in CDs has been studied and rationalized by NMR spectroscopy experiments and molecular modeling calculations. The credit of the presented protocol includes good yields and catalyst reusability and precludes the use of organic solvents.

Assessment the exposure effects of polycarbonate with X-ray radiation using spectroscopic techniques and molecular modeling calculations

Assessment the exposure effects of polycarbonate with X-ray radiation using spectroscopic techniques and molecular modeling calculations

Development and Comprehensive Benchmark of a High-Quality AMBER-Consistent Small Molecule Force Field with Broad Chemical Space Coverage for Molecular Modeling and Free Energy Calculation.

Biomolecular simulations have become an essential tool in contemporary drug discovery, and molecular mechanics force fields (FFs) constitute its cornerstone. Developing a high quality and broad coverage general FF is a significant undertaking that requires substantial expert knowledge and computing resources, which is beyond the scope of general practitioners. Existing FFs originate from only a limited number of groups and organizations, and they either suffer from limited numbers of training sets, lower than desired quality because of oversimplified representations, or are costly for the molecular modeling community to access. To address these issues, in this work, we developed an AMBER-consistent small molecule FF with extensive chemical space coverage, and we provide Open Access parameters for the entire modeling community. To validate our FF, we carried out benchmarks of quantum mechanics (QM)/molecular mechanics conformer comparison and free energy perturbation calculations on several benchmark data sets. Our FF achieves a higher level of performance at reproducing QM energies and geometries than two popular open-source FFs, OpenFF2 and GAFF2. In relative binding free energy calculations for 31 protein-ligand data sets, comprising 1079 pairs of ligands, the new FF achieves an overall root-mean-square error of 1.19 kcal/mol for ΔΔG and 0.92 kcal/mol for ΔG on a subset of 463 ligands without bespoke fitting to the data sets. The results are on par with those of the leading commercial series of OPLS FFs.

New 5-Substituted SN38 Derivatives: A Stability Study and Interaction with Model Nicked DNA by NMR and Molecular Modeling Methods.

The new 5-substituted SN-38 derivatives, 5(R)-(N-pyrrolidinyl)methyl-7-ethyl-10-hydroxycamptothecin (1) and its diastereomer 5(S) (2), were investigated using a combination of nuclear magnetic resonance (NMR) spectroscopy and molecular modeling methods. The chemical stability, configuration stability, and propensity to aggregate as a function of concentration were determined using 1H NMR. The calculated self-association constants (Ka) were found to be 6.4 mM-1 and 2.9 mM-1 for 1 and 2, respectively. The NMR experiments were performed to elucidate the interaction of each diastereomer with a nicked decamer duplex, referred to as 3. The calculated binding constants were determined to be 76 mM-1 and 150 mM-1 for the 1-3 and 2-3 complexes, respectively. NMR studies revealed that the interaction between 1 or 2 and the nicked decamer duplex occurred at the site of the DNA strand break. To complement these findings, molecular modeling methods and calculation protocols were employed to establish the interaction mode and binding constants and to generate molecular models of the DNA/ligand complexes.

Study on the photoinitiation mechanism of carbazole-based oxime esters (OXEs) as novel photoinitiators for free radical photopolymerization under near UV/visible-light irradiation exposure and the application of 3D printing

In this work, twenty-two oxime esters bearing different functional groups and based on carbazole as the chromophore were designed and synthesized as Type I photoinitiators. Interestingly, all structures mentioned in this work have never been reported before (even for their synthesis). These oxime esters were found to have good light absorption properties in the UV–visible range, and especially at 405 nm which is a reference wavelength in photopolymerization. Noticeably, several structures showed better photoinitiation abilities than the benchmark photoinitiator i.e. diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (TPO), evidencing the interest of these structures. In order to investigate the photoinitiation mechanism of the two series of oxime esters differing by the position of the photocleavable groups, electronic absorption spectra were determined by molecular modeling and density functional theory calculations. Photopolymerization abilities of the different oxime esters and release of CO2 during the polymerization experiments were determined by Real-Time Fourier Transformed Infrared (RT-FTIR). Active free radicals were characterized by mean of Electron Spin Resonance Spin Trapping (ESR-ST) experiments. On the basis of these different complementary experiments, chemical mechanisms occurring during photopolymerization could be proposed. Experimental results showed that the decarboxylation reaction occurring subsequent to the photocleavage of oxime esters had a beneficial effect on the photoinitiation ability. Finally, 3D printed objects were successfully obtained by using oxime esters exhibiting the best photoinitiating abilities.

Inspired dual functional adsorption films of armed molecules on copper

AbstractIn this study, double norfloxacin skeletons including the target armed molecules (DNs) displaying antibacterial and anticorrosion properties for copper in aqueous solutions were presented. The molecular modelling and material simulation calculations suggest that the target molecules could be adsorbed to copper surface, which was further demonstrated by attenuated total reflection infrared spectroscopy (ATR‐IR), X‐ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and scanning electron microscopy (SEM). The experimental results show that the copper surface which adsorbed the target armed molecules exhibited an excellent inhibitory effect on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The potentiodynamic polarization plots and electrochemical impedance spectroscopy demonstrate that the DNs of 0.100 mM achieved over 95% corrosion inhibition efficiency for copper in 0.5 M H2SO4 solution at 298 K. The results given in this study may guide us to achieve bacterial and corrosion resistances for copper based on the drug‐included armed molecules.

Diketo acid inhibitors of nsp13 of SARS-CoV-2 block viral replication

For RNA viruses, RNA helicases have long been recognized to play critical roles during virus replication cycles, facilitating proper folding and replication of viral RNAs, therefore representing an ideal target for drug discovery. SARS-CoV-2 helicase, the non-structural protein 13 (nsp13) is a highly conserved protein among all known coronaviruses, and, at the moment, is one of the most explored viral targets to identify new possible antiviral agents. In the present study, we present six diketo acids (DKAs) as nsp13 inhibitors able to block both SARS-CoV-2 nsp13 enzymatic functions. Among them four compounds were able to inhibit viral replication in the low micromolar range, being active also on other human coronaviruses such as HCoV229E and MERS CoV. The experimental investigation of the binding mode revealed ATP-non-competitive kinetics of inhibition, not affected by substrate-displacement effect, suggesting an allosteric binding mode that was further supported by molecular modelling calculations predicting the binding into an allosteric conserved site located in the RecA2 domain.

Synthesis and photochemistry of flavonol camphorsulfonates photoinitiator with different substituents

In this study, we synthesized five novel flavonol camphorsulfonates (HFSs) photoinitiators using a flavonol scaffold as the chromophore. These HFSs demonstrated photoinitiating properties in both one-component (Norrish Type I) and two-component photoinitiating systems, with high final reaction function conversion and excellent polymerization rates of acrylates in free radical photopolymerization. Additionally, HFSs exhibited thermal stability in thermogravimetric tests. To explain the photoinitiating mechanisms, we used various complementary approaches, including real-time FT-IR spectroscopy, UV–Vis absorption spectroscopy, fluorescence spectroscopy, analysis of photolysis products, cyclic voltammetry, free radical capture experiments and molecular modelling calculations.

Molecular and biological activities of metal oxide-modified bioactive glass

Bioactive glass (BG) was prepared by sol–gel method following the composition 60-(x) SiO2.34CaO.6P2O5, where x = 10 (FeO, CuO, ZnO or GeO). Samples were then studied with FTIR. Biological activities of the studied samples were processed with antibacterial test. Model molecules for different glass compositions were built and calculated with density functional theory at B3LYP/6-31 g(d) level. Some important parameters such as total dipole moment (TDM), HOMO/LUMO band gap energy (ΔE), and molecular electrostatic potential beside infrared spectra were calculated. Modeling data indicated that P4O10 vibrational characteristics are enhanced by the addition of SiO2.CaO due to electron rush resonating along whole crystal. FTIR results confirmed that the addition of ZnO to P4O10.SiO2.CaO significantly impacted the vibrational characteristics, unlike the other alternatives CuO, FeO and GeO that caused a smaller change in spectral indexing. The obtained values of TDM and ΔE indicated that P4O10.SiO2.CaO doped with ZnO is the most reactive composition. All the prepared BG composites showed antibacterial activity against three different pathogenic bacterial strains, with ZnO-doped BG demonstrating the highest antibacterial activity, confirming the molecular modeling calculations.

Synthesis, optical, electrochemical, and computational investigation of new cyanopyridine-centered organic dyads

Herein we report the molecular design, synthesis, and inclusive investigation of four novel di-anchored symmetric dyes (CP1-4) centered on electron deficient cyanopyridine scaffold as possible photosensitizers for DSSC application. These new chromogens (CP1-4) comprise a powerful electron-withdrawing cyanopyridine moiety linked with additional electron attracting functionalities such as cyanoacetic acid (CP1), 3-(carboxymethyl) rhodanine (CP2), 2,4,6-pyrimidinetrione (CP3), and 2,6-dihydroxy-2-mercaptopyrimidine (CP4), as effective acceptor/anchoring units via biphenyl donor units. Their in-depth optical and electrochemical behaviour were investigated to assess their suitability as photosensitizers. Further, the molecular modeling calculations were undertaken to understand their ground state properties and energy level potentials. The comprehensive studies revealed that they own all the requisites to performance as a potential photosensitizer for DSSC application.

Cumulants of net-strangeness multiplicity distributions at energies available at the BNL Relativistic Heavy Ion Collider

The higher-order cumulants of net-proton number, net-charge, and net-strangeness multiplicity distributions are widely studied to search for the quantum-chromodynamics critical point and extract the chemical freeze-out parameters in heavy-ion collisions. In this context, the event-by-event fluctuations of the net-strangeness multiplicity distributions play important roles in extracting the chemical freeze-out parameter in the strangeness sector. Due to having difficulties in detecting all strange hadrons event by event, the kaon ($K$) and lambda ($\Lambda$) particles serve as a proxy for the strangeness-related observables in heavy-ion collisions. We have studied the net-$K$, net-$\Lambda$, and net-($K$ + $\Lambda$) multiplicity distributions and calculated their different order of cumulants using the ultrarelativistic quantum molecular dynamics model and hadron resonance gas calculation. To adequately account for the net-strangeness cumulants, it has been found that the inclusion of resonance decay contributions in $K$ and $\Lambda$ is necessary.

Bio-Modifier: A Sustainable Suturing Technology at the Bitumen–Aggregate Interface

Premature failure at the bitumen–aggregate interface is attributed to the surface chemistry of stone aggregates. Bitumen modifiers with high affinity toward aggregates are often used to change the surface chemistry of aggregates, which in turn changes the type and strength of stones’ interactions with bitumen. Here, the mechanisms of action and the effects of an organosilane and bio-oil separately on the bitumen–aggregate interface, including their binding to aggregates from one side and to bitumen from the other side, were studied and compared. The binding of bio-oils and organosilanes to aggregates is well documented, as well as their efficacy as anti-stripping agents, but their binding to bitumen is not well understood. Using glass beads as a surrogate for siliceous stones, we obtained laboratory measurements of interfacial strength as measured by resistance to shear forces at the interface of bitumen and silica. Our laboratory measurements showed the highest value for the bitumen modified with bio-oil, followed by the control bitumen with no modification, and the lowest value for the bitumen modified with organosilane. Our molecular modeling calculations showed that the adhesion of bitumen molecules to silica coated with bio-oil was notably stronger (up to 72%) than the adhesion of bitumen molecules to silica coated with organosilane. The higher interfacial strength observed for bitumen with bio-oil is attributed to bio-oil having various functional groups with the ability to form hydrogen bonds and π–π interactions with the aromatic and polar components of bitumen. The study outcomes highlight the importance of modifiers’ ability to strongly interact with both aggregates and bitumen. The bio-oil modifier introduced in this work can form a robust bridge between bitumen and siliceous aggregates to improve the adhesive properties, enhancing the sustainability and durability of bituminous composites.

The XBB.1.5 slightly increase the binding affinity for host receptor ACE2 and exhibit strongest immune escaping features: molecular modeling and free energy calculation.

Introduction: The current XBB variant of SARS-CoV-2 with the strongest immune escaping properties is currently the most dominant variant circulating around the world. With the emergence of XBB global morbidities and mortalities have raised again. In the current scenario, it was highly required to delineate the binding capabilities of NTD of XBB subvariant towards human neutralizing antibodies and to dig out the binding affinity of RBD of XBB subvariant with ACE2 receptor. Materials and Methods: The current study uses molecular interaction and simulation-based approaches to decipher the binding mechanism of RBD with ACE2 and mAb interaction with NTD of the spike protein. Results: Molecular docking of the Wild type NTD with mAb revealed a docking score of -113.2 ± 0.7kcal/mol while XBB NTD docking with mAb reported -76.2 ± 2.3kcal/mol. On the other hand, wild-type RBD and XBB RBD with ACE2 receptor demonstrated docking scores of -115.0 ± 1.5kcal/mol and -120.8 ± 3.4kcal/mol respectively. Moreover, the interaction network analysis also revealed significant variations in the number of hydrogen bonds, salt-bridges, and non-bonded contacts. These findings were further validated by computing the dissociation constant (KD). Molecular simulation analysis such as RMSD, RMSF, Rg and hydrogen bonding analysis revealed variation in the dynamics features of the RBD and NTD complexes due to the acquired mutations. Furthermore, the total binding energy for the wild-type RBD in complex with ACE2 reported -50.10kcal/mol while XBB-RBD coupled with ACE2 reported -52.66kcal/mol respectively. This shows though the binding of XBB is slightly increased but due to the variation in the bonding network and other factors makes the XBB variant to enter into the host cell efficiently than the wild type. On the other hand, the total binding free energy for the wildtype NTD-mAb was calculated to be -65.94kcal/mol while for XBB NTD-mAb was reported to be -35.06kcal/mol respectively. The significant difference in the total binding energy factors explains that the XBB variant possess stronger immune evasion properties than the others variants and wild type. Conclusions: The current study provides structural features for the XBB variant binding and immune evasion which can be used to design novel therapeutics.