Computational Study Research Articles

Experimental and computational studies on possibility of using glucose diazacrown cryptand as a carrier for anticancer drugs busulfan and lomustine

AbstractDrug carriers play a very important role in pharmacy, especially in cancer therapy. Most drugs used in the treatment of cancer are characterized by poor solubility in water and lack of selectivity in their toxic effects on normal and cancer cells. Administration of the drug in the form of a complex with an appropriately selected carrier can significantly improve its therapeutic effect and reduce side effects. In this study, the possibility of using the cryptand L1, containing two diazacrown ethers and two saccharide groups, as a potential drug carrier is investigated. In order to determine whether it can form complexes with drugs, the cryptand L1 and its complexes with two anticancer drugs, busulfan (BSF) and lomustine (CCNU), were synthesized. Their selected structural and energetic properties were investigated using both experimental and computational methods. Additionally, water solubility and cytotoxicity tests were performed for all compounds. The measured 1H NMR spectra confirm that L1 forms complexes L1:BSF and L1:CCNU, the solubility of which in water appears to be much higher than that of the pure drugs. The results of DFT calculations made in water described with the implicit solvent model confirm high stability of L1:BSF and L1:CCNU and indicate that L1 forms with the drugs mainly non-inclusion complexes. However, additional tests with 20 H2O molecules explicitly included in the model suggest that both inclusion and non-inclusion forms can occur in a real solution. Cytotoxicity studies show that the macrocycle L1 is non-toxic towards both normal and cancer cells, and its complexes with drugs show greater selectivity towards cancer cells. Interestingly, while the cytotoxicity of the L1:BSF complex is stronger than that of pure BSF, the relationship is opposite in the case of L1:CCNU and CCNU. Therefore, L1 can be considered as a potential drug carrier, especially for those drugs that have weak activity on cancer cells.

Three Strikingly Different Crystal Habits of Tadalafil: Design, Characterization, Pharmaceutical Performance, and Computational Studies

Three Strikingly Different Crystal Habits of Tadalafil: Design, Characterization, Pharmaceutical Performance, and Computational Studies

Timing of resting zone parathyroid hormone-related protein expression affects maintenance of the growth plate during secondary ossification: a computational study.

Secondary ossification and maintenance of the growth plate are crucial aspects of long bone formation. Parathyroid hormone-related protein (PTHrP) has been implicated as a key factor in maintaining the growth plate, and studies suggest that PTHrP expression in the resting zone is closely related with formation of the secondary ossification center (SOC). However, details of the relationship between resting zone PTHrP expression and preservation of the growth plate remain unclear. In this study, we aim to investigate the role of resting zone PTHrP expression on maintenance of the growth plate using a computational method. We extend an existing continuum-based particle model of tissue morphogenesis to include PTHrP and Indian hedgehog (Ihh) signaling, allowing the model to capture biochemical and mechanical regulation of individual cell activities. Our model indicates that the timing of resting zone PTHrP expression-specifically the rate of increase in production at the onset of SOC formation-is potentially a crucial mechanism for maintenance of the growth plate.

Atomic Hydrogen Interaction with Transition Metal Surfaces: A High-Throughput Computational Study

Atomic Hydrogen Interaction with Transition Metal Surfaces: A High-Throughput Computational Study

Computational Characterization of the DAD Photoisomerization: Functionalization, Protonation, and Solvation Effects.

Photoswitches are becoming increasingly popular in pharmacology due to the possibility of modifying their activity with light. Hence, it is crucial to understand the photophysics of these compounds to identify promising light-activated drugs. We focused our study on DAD, an azobenzene derivative that, according to a previous experimental investigation, can restore visual function in blind mice due to trans-cis photoisomerization upon light absorption. With the present computational study, we aim to characterize the absorption spectrum of DAD, and to understand its photoisomerization mechanism by means of conformational search analysis, quantum mechanical (QM) and hybrid QM/continuum calculations, and classical molecular dynamics simulations. Moreover, we explored the effect of the derivation (DAD vs azobenzene), the protonation (DAD vs DADH22+, the two possible protonation states) and the solvation (vacuum vs water) on the photoisomerization. Similarly to azobenzene, we showed that the photoisomerization of both protonation states of DAD begin with the population of the bright S2 state. Then, it crosses to the S1 surface and relaxes along the rotation of the azo dihedral to a S1/S0 crossing point. The latter is close to a transition state that connects the trans and cis geometries on the ground state. Finally, our results suggested that amino derivation, nonprotonation and water solvation could improve the quantum yield of the photoisomerization.

Identification of potential natural product inhibitors against the Mpro enzyme of Covid-19: a computational study

Identification of potential natural product inhibitors against the Mpro enzyme of Covid-19: a computational study

Discovery of the First-in-Class Dual TSPO/Carbonic Anhydrase Modulators with Promising Neurotrophic Activity.

In searching for putative new therapeutic strategies to treat neurodegenerative diseases, the mitochondrial 18 kDa translocator protein (TSPO) and cerebral isoforms of carbonic anhydrase (CA) were exploited as potential targets. Based on the structures of a class of highly affine and selective TSPO ligands and a class of CA activators, both developed by us in recent years, a small library of 2-phenylindole-based dual TSPO/CA modulators was developed, able to bind TSPO and activate CA VII in the low micromolar/submicromolar range. The interaction with the two targets was corroborated by computational studies. Biological investigation on human microglia C20 cells identified derivative 3 as a promising lead compound worthy of future optimization due to its (i) lack of cytotoxicity, (ii) ability to stimulate TSPO steroidogenic function and activate CA VII, and (iii) ability to effectively upregulate gene expression of the brain-derived neurotrophic factor.

Force-Assisted Orbital Crossing in Mechanochemical Oxirane Ring Opening.

Polymer mechanochemistry induces chemical reactivity by applying a directed force, which can lead to unexpected reaction mechanisms. Strained cyclic molecules are often used in force-sensitive motifs because of the strong force coupling of ring-opening reactions. In this computational study, the force dependence of the ring-opening reactions of oxirane will be investigated. Density functional theory and multireference methods were used to investigate the electronic character of both symmetry-allowed and symmetry-forbidden reactions. In the latter case, an orbital crossing occurs during the reaction course, forcing the Woodward-Hoffmann-forbidden reaction to proceed via a diradical pathway. The performance of broken-symmetry density functional theory is evaluated and compares well to high-accuracy CASPT2, MRCI, and ic-MRCC computations. Due to the high ring strain, the barrier heights of both ring-opening reactions are steeply reduced by the application of an external force. Furthermore, the use of unsaturated linkers was shown to yield a significant reduction of the barrier heights, explaining previous experimental findings. Finally, we show through analysis of the PES topology how the external force transforms characteristic points such as saddle points and bifurcations, providing insights into force-dependent mechanism changes.

Gem-Difluorobicyclo[2.1.1]hexanes via Photochemical [2π + 2σ] Cycloaddition Initiated by Oxidative Activation of gem-Difluorodienes.

The incorporation of fluorine atoms into three-dimensional sp3-rich scaffolds represents an attractive tactic during bioisosteric evolution campaigns by endowing bioisosteric candidates with improved pharmacokinetic properties. Photo- or Lewis acid-mediated bicyclo[1.1.0]butane cycloaddition has offered an efficient approach for the construction of numerous regular bicyclo[n.1.1] scaffolds (n = 1-5) but remains a significant challenge to the synthesis of related 3D fluorinated scaffolds. Herein, we unveiled a photochemical single-electron oxidative strategy for gem-difluorodiene activation and subsequent [2π + 2σ] cycloaddition with bicyclo[1.1.0]butanes to provide a broad range of gem-difluorobicyclo[2.1.1]hexane scaffolds containing several post-transformable handles. A combination of experimental and computational mechanistic studies suggested that the conjugated π system of gem-difluorodiene plays important dual roles in promoting its preferential single-electron oxidation and stabilizing various radical-involved intermediates during the cyclization.

Light-Emitting Coordination Polymers: Stimuli-Responsive Gels, PMMA-Based Composite Films, and UV-Shielding.

Lanthanide-based light-emitting coordination polymers (CPs) and CP gels (CPGs) have significance for applications in optical systems, image processing/multiplexing, and optical sensors. In this study, we report two new luminescent CPs (EuL-CP (1) and TbL-CP (2)) and CPGs (EuL-gel (5) and TbL-gel (6)) using lanthanide(III) ions (Ln(III) = Eu(III) and Tb(III)) and 4-(4-carboxyphenyl)-2,2:6,2-terpyridine ligand (L) capable of forming stable thermoreversible gels. Probable structures of EuL-CP (1) and TbL-CP (2) and the formations of EuL-gel (5) and TbL-gel (6) are proposed based on adequate computational studies. The CPGs are stimuli-responsive and could be utilized as invisible security inks for encryption. Further, poly(methyl methacrylate) (PMMA) polymer doped with respective CPs (0.75 wt %) is found to be suitable for forming composite films with UV-shielding properties.

Vertically Expanded Crystalline Porous Covalent Organic Frameworks.

Covalent organic frameworks (COFs) can be developed for molecular confinement and separation. However, their proximate π stacks limit the interlayer distance to be only 3-6 Å, which is too small for guests to enter. As a result, COFs block access to the x-y space and limit guest entry/exit strictly to only the pores along the z direction. Therefore, the extended faces of each layer are hidden between layers, precluding any interactions with guest molecules. Here, we report a strategy for opening interlayer spaces of COFs to attain newly accessible nanospaces between layers. This becomes possible using coordination bonds to replace the conventional π-π stacks between layers. We demonstrate this concept by synthesizing two-dimensional covalent cobalt(II) porphyrin layers through topology-guided polymerization, which were piled up by bidentate axial pillars through coordination bonds with cobalt(II) porphyrin along the z direction, assembling vertically expanded COFs via a one-pot reaction. The resultant frameworks separate the layers with axial pillars and create discrete apertures between layers defined by the molecular length of the pillars. Consequently, the originally inaccessible interlayers are open for guest access, while the polygonal π planes are exposed to trigger various supramolecular interactions. Vapor sorption, breakthrough experiments, and computational studies mutually revealed that the vertically expanded frameworks with optimal interlayer slits induce additional interactions to discriminate benzene and cyclohexane and separate their mixtures efficiently under ambient conditions.

Innovative application of green surfactants as eco-friendly scale inhibitors in industrial water systems.

Scale deposition poses significant challenges in various industrial utilities, necessitating the development of eco-friendly scale inhibitors in line with environmental regulations. This study investigates the potential of two natural surfactants, Casein and Rhamnolipid, as innovative inhibitors for calcium carbonate (CaCO3) scale formation, offering an alternative to traditional water treatment chemicals. The anti-scaling characteristics of these two green surfactants were performed using conductivity and electrochemical impedance spectroscopy (EIS) techniques. Additionally, X-ray diffraction (XRD) and scanning electron microscopy (SEM) were utilized to analyze the morphology of CaCO3 crystals and understand the structural changes induced by surfactant interaction. The results revealed that Rhamnolipids significantly outperform Casein in suppressing scale formation, attributed to the adsorption of their multiple functional groups onto scale microcrystals. This adsorption modifies the crystal structure and inhibits further growth. Computational studies were employed to investigate the inhibition mechanism of these surfactants. The spatial and electrical configurations of optimal molecular structures are also analyzed using the Density Functional Theory (DFT) approach. Monte Carlo simulations on the CaCO3 (104) surface demonstrated that Rhamnolipids exhibit superior inhibition compared to Casein, as evidenced by their higher adsorption energy, indicating a more stable binding to the surface. Overall, this research highlights the potential of these natural surfactants as sustainable scale inhibitors, particularly in industries such as food and pharmaceuticals, thereby contributing to environmentally friendly water treatment solutions.

Computational Study on the Octahedral Surfaces of Magnetite Nanoparticles and Their Solvent Interaction.

Magnetite nanoparticles (MNPs) play an important role in geological and environmental systems because of their redox reactivity and ability to sequester a wide range of metals and metalloids. X-ray absorption spectroscopy conducted at metal and metalloid edges has suggested that the magnetite {111} faces of octahedrally shaped nanoparticles play a dominant role in the redox and sorption processes of these elements. However, studies directly probing the magnetite surfaces, especially in their fully solvated state, are scarce. Therefore, we investigated the speciation and stability over a wide Eh/pH range of octahedrally shaped MNPs of 2 nm size by means of Kohn-Sham density functional theory with Hubbard correction (DFT+U). By altering the protonation state of the crystals, a redox-sensitive response of the octahedrally coordinated Fe could be achieved. Furthermore, the preferential H distribution could be identified, highlighting the difference between the edges, vertices, and facets of the nanocrystals. Subsequently, the interactions of the MNPs with a solvent of pure water or a 0.5 M NaCl solution were studied by classical molecular dynamics (MD) simulations. Finally, a comparison of the corresponding macroscopic magnetite (111) surface to the investigated MNPs was conducted.

Evolution Enhances Kemp Eliminase Activity by Optimizing Oxyanion Stabilization and Conformational Flexibility.

The base-promoted Kemp elimination reaction has been used as a model system for enzyme design. Among the multiple computationally designed and evolved Kemp eliminases generated along the years, the HG3-to-HG3.17 evolutionary trajectory is particularly interesting due to the high catalytic efficiency of HG3.17 and the debated role of glutamine 50 (Gln50) as potential oxyanion stabilizer. This study aims to elucidate the structural and dynamic changes along the evolutionary pathway from HG3 to HG3.17 that contribute to improved catalytic efficiency. In particular, we evaluate key variants along the HG3 evolutionary trajectory via molecular dynamics simulations coupled to non-covalent interactions and water analysis. Our computational study indicates that HG3.17 can adopt a catalytically competent conformation promoted by a water-mediated network of non-covalent interactions, in which aspartate 124 is properly positioned for proton abstraction and both glutamine 50 and mutation cysteine 84 contribute to oxyanion stabilization. We find that HG3.17 exhibits a rather high flexibility of Gln50, which is regulated by the conformation adopted by the active site residue Trp44. This interplay between Gln50 and Trp44 positioning induced by distal active site mutations affects the water-mediated network of non-covalent interactions, Gln50 preorganization, and water content of the active site pocket.

A computational study of the size effect of SiO2 spherical nanoparticles in water solvent.

This study comprehensively describes the interaction between SiO2 spherical nanoparticles and water molecules as a solvent medium. Our goal is to provide valuable insights into the significance of nanoparticle size in understanding their behavior and the resulting changes in the physical properties of materials. Our results indicate that SiO2 nanoparticles exhibit a strong affinity for water, which increases with the nanoparticle size. Our investigation can be relevant for the design of new composite materials with applications ranging from medical prostheses to quantum electronics, optoelectronic devices, catalysis, and photoluminescence. We have concentrated on the study of the amorphous, where size effects seem to be more pronounced. A computational study was carried out within the molecular dynamics simulations framework available in the GROMACS-v2019.2 software, with force fields consistent with DFTand the CHARMM36 utilized in the molecular description of the systems. The water model used was the TIP3P implemented in CHARMM36 force fields. A comprehensive analysis of molecular interactions of various system configurations was performed, including radial distribution function (RDF), mean square displacement (RMSD), hydrogen bonding analysis,interfacial analysis, andstudying system size'seffect on mechanical properties.

Protective effects of Juglans regia oil on lead acetate-induced reprotoxicity in rats: an antioxidant, histological and computational molecular study.

Lead (Pb) is a metal that affects many body systems, primarily the male reproductive system. This study aimed to examine the phytochemical profiling and beneficial effects of Juglans regia oil (JRO) in alleviating lead-induced reprotoxicity-associated oxidative injury in rats. Adult male Wistar rats were randomly divided into four groups as follows: control group received no treatment, Pb group was exposed to 0.344 g kg-1 bw of Pb acetate, Pb + JRO group was co-treated with Pb plus walnut oil (0.9 g kg-1 bw) and JRO group received walnut oil only. Pb-treated rats showed significantly decreased gonado-somatic index, count and viability of sperm. Testosterone levels decreased in Pb-treated animals. Besides, Pb disrupted the oxidative/antioxidative status, the plasmatic lipase activity and testicular Pb content. Furthermore, Pb produced testis histopathological features, especially cell degeneration, atrophy and tubular disarrangement. Co-treatment with JRO was found to be effective for recovering the increased testicular oxidative damage-associated histological features in the Pb group. This was supported by the in silico modeling results. The in silico analyses revealed that JRO compounds bound androgen receptor and RAC-alpha serine/threonine kinase with high affinities, which together with pharmacokinetic properties and molecular interactions satisfactorily support the beneficial in vivo findings in the Pb + JRO group of rats. © 2024 Society of Chemical Industry.

SPOP-mediated RIPK3 destabilization desensitizes LPS/sMAC/zVAD-induced necroptotic cell death.

RIPK1/RIPK3-MLKL signaling molecules are fundamental in initiating necroptotic cell death, but their roles in the development of colon cancer are unclear. This study reports that RIPK3 interacted with SPOP, a component of the E3 ligase within the Cul3 complex. This interaction leads to K48-linked ubiquitination and subsequent proteasomal degradation of RIPK3. Two distinct degron motifs, PETST and SPTST, were identified within the linker domain of RIPK3 for SPOP. RIPK3 phosphorylations at Thr403 by PIM2 and at Thr412/Ser413 by ERK2 are essential to facilitate its interaction with SPOP. Computational docking studies and immunoprecipitation analyses showed that these PIM2 and ERK2 phosphorylations bolster the stability of the RIPK3-SPOP interaction. In particular, mutations of RIPK3 at the degron motifs extended the half-life of RIPK3 by preventing its phosphorylation and subsequent ubiquitination. The deletion of SPOP, which led to increased stability of the RIPK3 protein, intensified LPS/sMAC/zVAD-induced necroptotic cell death in colon cancer cells. These findings underscore the critical role of the SPOP-mediated RIPK3 stability regulation pathway in controlling necroptotic cell death.

Synthesis and redox catalysis of Carbodiphosphorane ligated stannylene.

Heavier group 14 carbene analogues, exhibiting transition-metal-like behavior, display remarkable capability for small molecule activation and coordination chemistry. However, their application in redox catalysis remains elusive. In this paper, we report the synthesis and isolation of a stannylene with carbodiphosphorane ligand. The nucleophilic reactivity at the divalent tin center is elucidated by computational and reactivity studies. Moreover, this stannylene exhibits catalytic activity in the hydrodefluorination reaction of fluoroarenes. Mechanistic investigations into the elementary steps confirm a SnII/SnIV redox cycle involving C-F oxidative addition, F/H ligand metathesis, and C-H reductive elimination. This low-valent SnII catalytic system resembles the classical transition metal catalysis. Notably, this represents metallomimetic redox catalysis utilizing carbene analogue with heavier group 14 element as a catalyst.

Riddelline from Tamarix articulate as a potential anti-bacterial lead compound for novel antibiotics discovery: A comprehensive computational and toxicological studies.

Tamarix articulate from the Tamaricaece family is a halophytic plant. This plant is commonly called Athal or Tamarix in different Arabic and Asian countries. Due to the high load of polyphenolic phytochemicals, the plant has been used as a therapeutic option against several diseases for decades. The plant is an anti-inflammatory, anti-bacterial, anti-viral, anti-cancer, anti-oxidant, and anti-inflammatory. In this work, the 222 phytochemical compounds of T. articulate from our previous study are used in different bioinformatic and biophysics techniques to explore their biological potency against different anti-bacterial, anti-cancer and anti-viral targets. By doing so, it was found that Riddelline ranked as the best binding molecule of biological macromolecules selected herein in particular the bacterial targets. The binding energy value of the compound for the KdsA enzyme was -14.64 kcal/mol, KdsB (-13.09 kcal/mol), MurC (-13.67 kcal/mol), MurD (-13.54 kcal/mol), MurF (-14.20 kcal/mol), Polo-like kinase 1 (Plk1) (-12.34 kcal/mol), Bcl-2 protein (-13.39 kcal/mol), SARS-CoV-2 main protease enzyme (-12.67 kcal/mol), and Human T cell leukemia virus protease (-13.67 kcal/mol). The mean Rg value of KdsA-Riddelline complex and KdsA-FPE complex is 32.67 Å, and average RMSD of KdsA-Riddelline complex and KdsA-FPE complex is 2.31 Å, respectively. The binding energy complexes was found to be dominated by van der Waals (-71.98 kcal/mol for KdsA-Riddelline complex and -65.09 kcal/mol for KdsA-FPE complex). The lead compound was also unveiled to show favorable druglike properties and pharmacokinetics. Together, the data suggest the good anti-bacterial activities of the T. articulate phytochemicals and thus can be subjected to experimental in vitro and in vivo investigations.

Discontinuity-Induced Dynamics in the Conductance-Based Adaptive Exponential Integrate-and-Fire Model.

In this article, we present a computational study of the Conductance-Based Adaptive Exponential (CAdEx) integrate-and-fire neuronal model, focusing on its multiple timescale nature, and on how it shapes its main dynamical regimes. In particular, we show that the spiking and so-called delayed bursting regimes of the model are triggered by discontinuity-induced bifurcations that are directly related to the multiple-timescale aspect of the model, and are mediated by canard solutions. By means of a numerical bifurcation analysis of the model, using the software package COCO, we can precisely describe the mechanisms behind these dynamical scenarios. Spike-increment transitions are revealed. These transitions are accompanied by a fold and a period-doubling bifurcation, and are organised in parameter space along an isola periodic solutions with resets. Finally, we also unveil the presence of a homoclinic bifurcation terminating a canard explosion which, together with the presence of resets, organises the delayed bursting regime of the model.