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Background: Since December 2019, a global crisis has unfolded with the emergence of a new strain of coronavirus known as SARS-CoV-2. This pandemic has afflicted hundreds of millions of people worldwide, resulting in millions of fatalities. In response to this urgent healthcare crisis, extensive efforts have been made to discover inhibitors of the COVID-19 virus. Given the structural similarities between SARS-CoV-2 and HCV, drugs approved by the FDA for treating HCV were selected and subjected to in silico testing against the SARS-CoV-2 virus, with Remdesivir used as the standard for validation. Drug repurposing and phytochemical testing have also been conducted to identify potential candidates capable of inhibiting or suppressing the infection caused by the coronavirus. The time constraints imposed by the pandemic necessitated the in silico analysis of existing drug molecules against the coronavirus. Eleven HCV drugs approved by the FDA, along with one RNA synthesis inhibitor antibiotic drug, were tested using the in silico method due to their structural similarities with HCV and the SARS-CoV-2 virus. Results: Molecular docking and MD simulation studies were performed for all selected compounds. Binding energies, root-mean-square deviation, root-mean-square fluctuation, solvent-accessible surface area, radius of gyration, and molecular mechanics generalized born surface area were calculated. Based on docking and MD simulation studies all the selected compounds have shown good binding energy values with Mpro (PDB ID: 6LU7). No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA. Conclusions: This study shows that FDA-approved HCV drugs can be used as for SARS-COVID-19 inhibitors. [ABSTRACT FROM AUTHOR]

The protein tyrosine phosphatase 1B (PTP1B) is a critical therapeutic target for type 2 diabetes mellitus (T2DM). Many PTP1B inhibitors have been reported, however, most of them lack high specificity and have adverse effects. Designing effective PTP1B inhibitors requires understanding the molecular mechanism of action between inhibitors and PTP1B. To this end, molecular dynamics (MD) simulations and molecular mechanics Poisson Boltzmann Surface Area (MM-PB/ SA) methods were used to observe the binding patterns of compounds with similar pentacyclic triterpene parent ring structures but different inhibition abilities. Through structure and energy analysis, we found that the positions of cavities and substituents significantly affect combining capacity. Besides, we constructed a series of potential inhibitor molecules using LUDI and rational drug design methods. The ADMET module of Discovery Studio 2020 was used to predict the properties of these inhibitor molecules. Lastly, we obtained compounds with low toxicity and significant inhibitory activity. The study will contribute to the treatment of T2DM. [ABSTRACT FROM AUTHOR]

Cancer remains a severe global health problem, with its incidence constantly increasing.. Among many varieties of cancer, breast cancer persists as a prevalent global health concern, with its occurrence continually ascending. Among women, breast cancer is a significant cause of illness and death globally. This study examined the antioxidant and anticancer effects of two resynthesized benzoxazine derivatives, OBOP‐01 and OBOP‐02, on human breast cancer cells. The chemicals investigated had intense antioxidant action against DPPH, H2O2, and ABTS free radicals. Furthermore, we evaluated cell viability by converting yellow MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide) into purple formazan, dependent on mitochondrial function. Both compounds had IC50 values of 1.52±0.02 mM and 1.72±0.02 mM respectively. Moreover, toxicity predictions using the ProTox‐III webserver showed that the benzoxazines studied have lower LD50 values compared to doxorubicin, suggesting greater safety. We also used Density Functional Theory (DFT) to analyze OBOP‐01 and OBOP‐02′s electrical interactions and properties. Gaining insight into these interactions is essential for understanding the compounds′ potential applications and properties. According to theoretical studies using molecular docking, the derivatives may interact with estrogen receptor alpha (ERα) (ID: 7NDO), a key target molecule in the development of breast cancer. Additionally, the complex OBOP‐01 – ERα′s molecular dynamics simulations were conducted for 100 nanoseconds. These simulations revealed essential details regarding the complex's dynamic behavior in a physiological system. [ABSTRACT FROM AUTHOR]

This study explores the repurposing of Food and Drug Administration (FDA)-approved drugs as potential inhibitors of SARS-CoV-2 papain-like protease (PLpro), a critical enzyme for viral replication. Initially, 3009 FDA-approved drugs were screened to identify candidates structurally similar to the co-crystallized ligand XT7 in the SARS-CoV-2 PLpro complex (PDB ID: 7LBR). A fingerprint analysis narrowed the selection to the top 5% (150 drugs) most structurally akin to XT7, followed by a more refined structural similarity test that identified the top 1% (30 drugs). Molecular docking studies highlighted several compounds with strong binding affinities to the SARS-CoV-2 PLpro. Notably, Fedratinib exhibited a particularly robust binding energy of -20.54 kcal/mol and was chosen for further investigation. Subsequent molecular dynamics (MD) simulations over 100 ns confirmed the stability and efficacy of Fedratinib’s binding, as evidenced by favorable energetic and dynamic profiles. The molecular mechanics-generalized born surface area (MM-GBSA) calculations corroborated these findings, revealing a binding energy of −24.36 kcal/mol. Additionally, PLIP, ProLIF, and PCAT analyses further validated the stability and interactions of the PLpro-Fedratinib complex observed during the MD simulations. Overall, our results indicate that Fedratinib, an FDA-approved drug, demonstrates promising potential as an inhibitor of SARS-CoV-2 PLpro, warranting further in vitro and in vivo experimental validation as well as potential clinical evaluation. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations were carried out to study the structural and diffusion properties of a cyanobiphenyl monolayer composed of pentyl cyano biphenyl (5CB) and pentyloxy cyano biphenyl (5OCB) molecules on a graphene surface coated with alkane and alcohol molecules. To investigate the diffusion properties of 5CB and 5OCB molecules on the graphene surface, the molecules of pentane (C5) and dodecane (C12) from alkanes and dodecanol (C12OH) from alcohols with a polar hydroxyl (−OH) terminal functional group were chosen as orienting surfactant molecules. It was found that the diffusion ability of cyanobiphenyl molecules in a graphene substrate coated with alkane and alcohol molecules depends on the chain length of these molecules and on the presence of polar hydroxyl –OH terminal groups. With an increase in the length of alkane molecules from C5 to C12, the value of the diffusion coefficient Dz5CB (or Dz5OCB), it decreases slightly, while the presence of the polar hydroxyl −OH terminal group leads to a significant decrease in this diffusion coefficient of cyanobiphenyl molecules. [ABSTRACT FROM AUTHOR]

BACKGROUND: Odorant‐binding proteins (OBPs) in insects are key to detection and recognition of external chemical signals associated with survival. OBP7 in Spodoptera frugiperda's larval stage (SfruOBP7) may search for host plants by sensing plant volatiles, which are important sources of pest attractants and repellents. However, the atomic‐level basis of binding modes remains elusive. RESULTS: SfruOBP7 structure was constructed through homology modeling, and complex models of six plant volatiles ((E)‐2‐hexenol, α‐pinene, (Z)‐3‐hexenyl acetate, lauric acid, O‐cymene and 1‐octanol) and SfruOBP7 were obtained through molecular docking. To study the detailed interactions between the six plant volatile molecules and SfruOBP7, we conducted three 300 ns molecular dynamics simulations for each study object. The correlation coefficients between binding free energy obtained by molecular mechanics/generalized Born surface area together with solvated interaction energy methods and experimental values are 0.90 and 0.88, respectively, showing a good correlation. By comparing binding free energy along with interaction patterns between SfruOBP7 and the six volatile molecules, hotspot residues of SfruOBP7 when binding with different volatile molecules were determined. Hydrophobic interactions stemming from van der Waals interactions play a significant role in SfruOBP7 and these plant volatile systems. CONCLUSION: The optimized three‐dimensional structure of SfruOBP7 and its binding modes with six plant volatiles revealed their interactions, thus providing a means for estimating the binding energies of other plant volatiles. Our study will help to guide the rational design of effective and selective insect attractants. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

This research begins with the initial assessment of key physical properties—density (ρ), speed of sound (u), and refractive index (nD) in binary aqueous solutions of dorzolamide hydrochloride. These properties were measured in solutions with varying molalities, ranging from 0.0 to 0.0276, under standard atmospheric conditions and at temperatures between 300.15 and 320.15 K. From these measurements, we were able to calculate a range of important parameters, including the apparent molar volume (Vϕ), its limiting values ( V ϕ 0 ), limiting apparent molar expansivity ( E ϕ 0 ), Helper's constant ( ∂ 2 V ϕ 0 ∂ T 2 ), apparent molar isentropic compression (κϕ), and its limiting values ( κ ϕ 0 ), specific refraction (RD), molar refraction (RM), and hydration number (nh). These calculated values provided insights into the strong interactions between the solute and solvent in the liquid system. They also shed light on the presence of various molecular interactions, such as inter- and intramolecular hydrogen bonds, dipole–dipole, and dipole-induced-dipole interactions, as well as the ability of the solute to influence the structure of the surrounding water molecules. Additionally, we derived the densities of dorzolamide hydrochloride solutions from molecular dynamics (MD) simulations, which showed a strong correlation with our experimental findings, underscoring the reliability of MD simulations in such studies. In the end, our combined study on dorzolamide hydrochloride in water demonstrates that it shapes structures because it has lower volumetric properties and stronger hydrogen bonds in MD simulations. More alchemical free energy calculations show that there are big changes in solvation energies. This is important for understanding how dorzolamide hydrochloride works in water. [ABSTRACT FROM AUTHOR]

D2 is a structural and cooperative domain of Thermotoga maritima Arginine Binding Protein, that possesses a remarkable conformational stability, with a denaturation temperature of 102.6°C, at pH 7.4. The addition of potassium thiocyanate causes a significant decrease in the D2 denaturation temperature. The interactions of thiocyanate ions with D2 have been studied by means of isothermal titration calorimetry measurements and molecular dynamics simulations. It emerged that: (a) 20–30 thiocyanate ions interact with the D2 surface and are present in its first solvation shell; (b) each of them makes several contacts with protein groups, both polar and nonpolar ones. The addition of guanidinium thiocyanate causes a marked destabilization of the D2 native state, because both the ions are denaturing agents. However, on adding to the solution containing D2 and guanidinium thiocyanate a stabilizing agent, such as TMAO, sucrose or sodium sulfate, a significant increase in denaturation temperature occurs. The present results confirm that counteraction is a general phenomenon for globular proteins. [ABSTRACT FROM AUTHOR]

AbstractModeling antioxidants for improved human health is a prime area of research. Inclusion complexes exhibit antioxidant activity. Supramolecular scaffolds like calixtyrosol are anticipated to have considerable antioxidant and therapeutic activity. In this study, we have designed 30 polyphenolic metacyclophanes and investigated their antioxidant properties. Exceptional O─H bond dissociation energy of 44 kcal/mol is reported for a metacyclophane with acyl urea linkage. This may be explained through a cooperative effect of localization of spin density distribution and an intramolecular hydrogen bonding of the corresponding radical. Further, the pharmacokinetics and toxicity analysis screened eight drug-like candidates. The interaction of the eight screened molecules with the Lysozyme transport protein and SOD protein has been studied using the molecular docking approach. Lastly, the MD simulations are performed to analyze the conformational changes of the transport protein after complexation with the proposed molecules. Comprehensive analyses including density functional studies of physiological parameters, favorable pharmacokinetics, toxicity, molecular docking, and MD simulations affirmed polyphenolic metacyclophane XXI as a radical scavenging and drug-like candidate. [ABSTRACT FROM AUTHOR]

This study investigates the nanostructure of two protic ionic liquids (PILs), [N0 0 0 3][C3CO2] and [N0 0 0 4][C2CO2], with similar polar head groups but varying alkyl chain lengths. An X-ray scattering technique and molecular dynamics simulations have been utilized to characterize the bulk and interfacial properties of these PILs. The findings suggest that the nanostructure of the PILs is primarily determined by the electrostatic forces between charged functional groups playing a dominant role. Despite differences in the alkyl chain lengths, the PILs possess remarkably similar nanostructures. Extending our investigation, we report the impact of water on the nanostructure. Our findings reveal that the addition of water disrupts interactions between cations and anions, weakening Coulombic forces. The disruptive behavior is attributed to the establishment of hydrogen bonds between water and ions. This comprehensive approach provides valuable insights into the nuanced factors shaping the nanostructure of these PILs, which are crucial for tailoring their applications in synthetic chemistry, catalysis, and beyond. [ABSTRACT FROM AUTHOR]

A DNA tumor virus called Epstein–Barr virus (EBV) is the cause of 1–2% of human cancers. EBV-associated carcinogenesis is caused by a persistent latent infection. The shortage of antiviral medications or vaccinations to control the virus led to a significant percentage of critically sickness individuals needing to be hospitalized. In the absence of an effective vaccine and approved drug, there is an immediate need for treatments that can combat EBV infection. Epstein–Barr nuclear antigen 1 (EBNA1) is continually expressed in all malignancies linked to EBV; it is a desirable target for curative interference. Herein, natural product compounds from the Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products (NuBBE) database were mined to identify potent EBNA1 inhibitors. The performance of the molecular docking technique was initially assessed in expecting the ligand-target binding pose according to the available experimental data. On the basis of the estimated docking protocol, the NuBBE database was virtually screened toward the EBNA1 protein, and the natural compounds with binding scores less than KWG (calc. -7.8 kcal/mol) were subjected to molecular dynamics (MD) simulations followed by binding energy (ΔGbinding) calculation using MM/GBSA approach. Based on binding energy computations, NuBBE1460 revealed superior ΔGbinding with a value of −36.2 kcal/mol, compared to KWG (calc. -32.4 kcal/mol). Post-MD analyses displayed a high steadiness of NuBBE1460 within the EBNA1 protein binding pocket. Furthermore, the physicochemical, pharmacokinetic and toxicity features of the identified compound were predicted, demonstrating high degrees of its oral bioavailability. The energetical and geometrical properties of NuBBE1460 were calculated using the DFT method. Conclusively, this study offers NuBBE1460 obtained from natural sources as a lead EBNA1 inhibitor for future investigation and development as a therapeutic for EBV. [ABSTRACT FROM AUTHOR]

The biocatalytic degradation of poly(ethylene terephthalate) (PET) through enzymatic methods has garnered considerable attention due to its environmentally friendly and non-polluting nature, as well as its high specificity. While previous efforts in enhancing IsPETase performance have focused on amino acid substitutions in protein engineering, we introduced an amino acid insertion strategy in this work. By inserting a negatively charged acidic amino acid, Glu, at the right-angle bend of IsPETase, the binding capability between the enzyme's active pocket and PET was improved. The resulted mutant IsPETase9394insE exhibited enhanced hydrolytic activity towards PET at various temperatures ranging from 30 to 45 ℃ compared with the wild-type IsPETase. Notably, a 10.04-fold increase was observed at 45 ℃. To further enhance PET hydrolysis, different carbohydrate-binding modules (CBMs) were incorporated at the C-terminus of IsPETase9394insE. Among these, the fusion of CBM from Verrucosispora sioxanthis exhibited the highest enhancement, resulting in a 1.82-fold increase in PET hydrolytic activity at 37 ℃ compared with the IsPETase9394insE. Finally, the engineered variant was successfully employed for the degradation of polyester filter cloth, demonstrating its promising hydrolytic capacity. In conclusion, this research presents an alternative enzyme engineering strategy for modifying PETases and enriches the pool of potential candidates for industrial PET degradation. [ABSTRACT FROM AUTHOR]

In the realm of parasitology, autophagy has emerged as a critical focal point, particularly in combating Leishmaniasis. Central to this endeavour is the recognition of the protein ATG8 as pivotal for the survival and infectivity of the parasitic organism Leishmania major, thereby making it a potential target for therapeutic intervention. Consequently, there is a pressing need to delve into the structural characteristics of ATG8 to facilitate the design of effective drugs. In this study, our efforts centered on the purification of ATG8 from Leishmania major, which enabled novel insights into its structural features through meticulous spectroscopic analysis. We aimed to comprehensively assess the stability and behaviour of ATG8 in the presence of various denaturants, including urea, guanidinium chloride, and SDS-based chemicals. Methodically, our approach included secondary structural analysis utilizing CD spectroscopy, which not only validated but also augmented computationally predicted structures of ATG8 reported in previous investigations. Remarkably, our findings unveiled that the purified ATG8 protein retained its folded conformation, exhibiting the anticipated secondary structure. Moreover, our exploration extended to the influence of lipids on ATG8 stability, yielding intriguing revelations. We uncovered a nuanced perspective suggesting that targeting both the lipid composition of Leishmania major and ATG8 could offer a promising strategy for future therapeutic approaches in combating leishmaniasis. Collectively, our study underscores the importance of understanding the structural intricacies of ATG8 in driving advancements towards the development of targeted therapies against Leishmaniasis, thereby providing a foundation for future investigations in this field. [ABSTRACT FROM AUTHOR]

The emergence of drug-resistance-inducing mutations in Hepatitis C virus (HCV) coupled with genotypic heterogeneity has made targeting NS3/4A serine protease difficult. In this work, we investigated the mutagenic variations in the binding pocket of Genotype 3 (G3) HCV NS3/4A and evaluated ligands for efficacious inhibition. We report mutations at 14 positions within the ligand-binding residues of HCV NS3/4A, including H57R and S139P within the catalytic triad. We then modelled each mutational variant for pharmacophore-based virtual screening (PBVS) followed by covalent docking towards identifying a potential covalent inhibitor, i.e., cpd-217. The binding stability of cpd-217 was then supported by molecular dynamic simulation followed by MM/GBSA binding free energy calculation. The free energy decomposition analysis indicated that the resistant mutants alter the HCV NS3/4A–ligand interaction, resulting in unbalanced energy distribution within the binding site, leading to drug resistance. Cpd-217 was identified as interacting with all NS3/4A G3 variants with significant covalent docking scores. In conclusion, cpd-217 emerges as a potential inhibitor of HCV NS3/4A G3 variants that warrants further in vitro and in vivo studies. This study provides a theoretical foundation for drug design and development targeting HCV G3 NS3/4A. [ABSTRACT FROM AUTHOR]

The human aryl hydrocarbon receptor (AhR), a ligand‐dependent transcription factor, plays a pivotal role in a diverse array of pathways in biological and pathophysiological events. This position AhR as a promising target for both carcinogenesis and antitumor strategies. In this study we utilized computational modeling to screen and identify FDA‐approved drugs binding to the allosteric site between α2 of bHLH and PAS‐A domains of AhR, with the aim of inhibiting its canonical pathway activity. Our findings indicated that nilotinib effectively fits into the allosteric pocket and forms interactions with crucial residues F82, Y76, and Y137. Binding free energy value of nilotinib is the lowest among top hits and maintains stable within its pocket throughout entire (MD) simulations time. Nilotinib has also substantial interactions with F295 and Q383 when it binds to orthosteric site and activate AhR. Surprisingly, it does not influence AhR nuclear translocation in the presence of AhR agonists; instead, it hinders the formation of the functional AhR‐ARNT‐DNA heterodimer assembly, preventing the upregulation of regulated enzymes like CYP1A1. Importantly, nilotinib exhibits a dual impact on AhR, modulating AhR activity via the PAS‐B domain and working as a noncompetitive allosteric antagonist capable of blocking the canonical AhR signaling pathway in the presence of potent AhR agonists. These findings open a new avenue for the repositioning of nilotinib beyond its current application in diverse diseases mediated via AhR. [ABSTRACT FROM AUTHOR]

Background: Breast cancer, a leading cause of female mortality, is closely linked to mutations in estrogen receptor beta (ESR2), particularly in the ligand‐binding domain, which contributed to altered signaling pathways and uncontrolled cell growth. Objectives/Aims: This study investigates the molecular and structural aspects of ESR2 mutant proteins to identify shared pharmacophoric regions of ESR2 mutant proteins and potential therapeutic targets aligned within the pharmacophore model. Methods: This study was initiated by establishing a common pharmacophore model among three mutant ESR2 proteins (PDB ID: 2FSZ, 7XVZ, and 7XWR). The generated shared feature pharmacophore (SFP) includes four primary binding interactions: Hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), hydrophobic interactions (HPho), and Aromatic interactions (Ar), along with halogen bond donors (XBD) and totalling 11 features (HBD: 2, HBA: 3, HPho: 3, Ar: 2, XBD: 1). By employing an in‐house Python script, these 11 features distributed into 336 combinations, which were used as query to isolate a drug library of 41,248 compounds and subjected to virtual screening through the generated SFP. Results: The virtual screening demonstrated 33 hits showing potential pharmacophoric fit scores and low RMSD value. The top four compounds: ZINC94272748, ZINC79046938, ZINC05925939, and ZINC59928516 showed a fit score of more than 86% and satisfied the Lipinski rule of five. These four compounds and a control underwent molecular (XP Glide mode) docking analysis against wild‐type ESR2 protein (PDB ID: 1QKM), resulting in binding affinity of −8.26, −5.73, −10.80, and −8.42 kcal/mol, respectively, along with the control −7.2 kcal/mol. Furthermore, the stability of the selected candidates was determined through molecular dynamics (MD) simulations of 200 ns and MM‐GBSA analysis. Conclusion: Based on MD simulations and MM‐GBSA analysis, our study identified ZINC05925939 as a promising ESR2 inhibitor among the top four hits. However, it is essential to conduct further wet lab evaluation to assess its efficacy. [ABSTRACT FROM AUTHOR]

This study starts by evaluating essential physical characteristics—density (ρ), sound velocity (u), and refractive index (nD)—in binary mixtures of Moxifloxacin Hydrochloride with water. We measured these properties in solutions with different concentrations, from 0.0 to 0.05 molalities, under normal atmospheric pressure and at temperatures from 305.15 to 320.15 K. From these measurements, we were able to calculate a range of important parameters, including the apparent molar volume V ϕ , its limiting values V ϕ 0 , limiting apparent molar expansibility E ϕ 0 , Hepler's constant ∂ 2 V ϕ 0 ∂ T 2 , apparent molar adiabatic compressibility k ϕ and its limiting values k ϕ 0 , specific refraction R D , molar refraction R M and hydration number n h . The calculated values demonstrated dominant solute–solvent interactions in the liquid mixture in this study. These findings indicated that molecules interact through hydrogen bonds, dipole–dipole interactions, and dipole-induced dipole interactions. They also showed how the solute influences the structure of water molecules. Moxifloxacin Hydrochloride (MOX) solution densities have been determined by MD simulations. These simulations matched our experimental data, proving MD simulation's effectiveness in such investigations. Finally, our in-depth research of MOX in water shows that it changes the way structures are made because it has lower volumetric properties and stronger hydrogen bonds, as seen in MD simulations. Solvation energies changed a lot when we did more calculations of alchemical free energy. These changes are very important for understanding how MOX behaves in water. [ABSTRACT FROM AUTHOR]

Malaria is the most severe and common parasitic infection, with P. falciparum responsible for the majority of cases and deaths each year. As anti‐malarial drug resistance continues to increase, novel compounds with anti‐ P. falciparum activity must be identified. In search of a new molecule to cure the resistant malarial parasite, a total of 1,70,269 ligands from the Asinex BioDesign library 2021.2 were virtually screened using AutoDock Vina against wild‐type P. falciparum dihydrofolate reductase‐thymidylate synthase (PfDHFR‐TS). The computational molecular modeling investigations indicated the discovery of seventeen new compounds (2‐18) with higher binding energy compared to the PfDHFR‐TS inhibitor, pyrimethamine (1). Furthermore, the study employing drug‐likeness criteria and their ADMET profile suggested that these hits were the most promising drug candidates due to higher absorption and druggability. Furthermore, GROMACS 2023.4 was used to perform the molecular dynamics simulations on the foremost compound (2) having sufficient stability, leading to a key step towards the search of novel PfDHFR‐TS inhibitors against malaria. [ABSTRACT FROM AUTHOR]

Atypical Chemokine Receptor 3 (ACKR3) belongs to the G protein-coupled receptor family but it does not signal through G proteins. The structural properties that govern the functional selectivity and the conformational dynamics of ACKR3 activation are poorly understood. Here, we combined hydrogen/deuterium exchange mass spectrometry, site-directed mutagenesis, and molecular dynamics simulations to examine the binding mode and mechanism of action of ACKR3 ligands of different efficacies. Our results show that activation or inhibition of ACKR3 is governed by intracellular conformational changes of helix 6, intracellular loop 2, and helix 7, while the DRY motif becomes protected during both processes. Moreover, we identified the binding sites and the allosteric modulation of ACKR3 upon β-arrestin 1 binding. In summary, this study highlights the structure-function relationship of small ligands, the binding mode of β-arrestin 1, the activation dynamics, and the atypical dynamic features in ACKR3 that may contribute to its inability to activate G proteins. [ABSTRACT FROM AUTHOR]

The discovery of mechanically soft solid‐state materials with fast Mg‐ion conduction is crucial for the development of solid‐state magnesium batteries. In this paper, novel magnesium gallium halide compounds are reported that achieve high ionic conductivity of 0.47 mS cm−1 at room temperature. These Mg‐ion conductors obtained by ball milling Mg and Ga salts exhibit clay‐like mechanical properties, enabling intimate contact at the electrode–electrolyte interface during battery cycling. With a combination of experimental and computational analysis, this study identifies that the soft‐clay formation is induced by partial anion exchange during milling. This partial anion exchange creates undercoordinated magnesium ions in a chlorine‐rich environment, yielding fast Mg‐ion conduction. This work demonstrates the potential of clay‐like halide electrolytes for all‐solid‐state magnesium batteries, with possible further extension to other multivalent battery systems. [ABSTRACT FROM AUTHOR]

Abstract Background Since December 2019, a global crisis has unfolded with the emergence of a new strain of coronavirus known as SARS-CoV-2. This pandemic has afflicted hundreds of millions of people worldwide, resulting in millions of fatalities. In response to this urgent healthcare crisis, extensive efforts have been made to discover inhibitors of the COVID-19 virus. Given the structural similarities between SARS-CoV-2 and HCV, drugs approved by the FDA for treating HCV were selected and subjected to in silico testing against the SARS-CoV-2 virus, with Remdesivir used as the standard for validation. Drug repurposing and phytochemical testing have also been conducted to identify potential candidates capable of inhibiting or suppressing the infection caused by the coronavirus. The time constraints imposed by the pandemic necessitated the in silico analysis of existing drug molecules against the coronavirus. Eleven HCV drugs approved by the FDA, along with one RNA synthesis inhibitor antibiotic drug, were tested using the in silico method due to their structural similarities with HCV and the SARS-CoV-2 virus. Results Molecular docking and MD simulation studies were performed for all selected compounds. Binding energies, root-mean-square deviation, root-mean-square fluctuation, solvent-accessible surface area, radius of gyration, and molecular mechanics generalized born surface area were calculated. Based on docking and MD simulation studies all the selected compounds have shown good binding energy values with Mpro (PDB ID: 6LU7). No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA. Conclusions This study shows that FDA-approved HCV drugs can be used as for SARS-COVID-19 inhibitors.

Molecular descriptors characterize the biological, physical, and chemical properties of molecules and have long been used for understanding molecular interactions and facilitating materials design. Some of the most robust descriptors are derived from geometrical representations of molecules, called 3-dimensional (3D) descriptors. When calculated from molecular dynamics (MD) simulation trajectories, 3D descriptors can also capture the effects of operating conditions such as temperature or pressure. However, extracting 3D descriptors from MD trajectories is non-trivial, which hinders their wide use by researchers developing advanced quantitative-structure-property-relationship models using machine learning. Here, we describe a suite of open-source Python-based post-processing routines, called PyL3dMD, for calculating 3D descriptors from MD simulations. PyL3dMD is compatible with the popular simulation package LAMMPS and enables users to compute more than 2000 3D molecular descriptors from atomic trajectories generated by MD simulations. PyL3dMD is freely available via GitHub and can be easily installed and used as a highly flexible Python package on all major platforms (Windows, Linux, and macOS). A performance benchmark study used descriptors calculated by PyL3dMD to develop a neural network and the results showed that PyL3dMD is fast and efficient in calculating descriptors for large and complex molecular systems with long simulation durations. PyL3dMD facilitates the calculation of 3D molecular descriptors using MD simulations, making it a valuable tool for cheminformatics studies.

In the current study, the most stable optimized structure of the named compound 5-(furan-2-ylmethylidene) thiazolo[3,4-a] benzimidazole-2-thione (FThBZ) was determined using the B3LYP/6-311++G(d,p) basis set. The nature of molecular interactions between molecules in the crystal via different type of bonds was investigated using Lattice Energy analysis and non-covalent reduced density gradient (NC-RDG) and Fukui functions are performed to study the chemical reactivity of the compound. The dipole moment values, first and second order polarizability and hyperpolarizability of the title compound were calculated. A symptom of Alzheimer's is the appearance of amyloid plaques, or senile plaques: made up of aggregates of beta-amyloid peptide between nerve cells. To overcome this effect, there is a need for a potent and effective inhibitor that inhibits the proper functioning of amyloid precursor protein (APP). In this regard, we conducted an in silico docking and molecular dynamics simulation study. [ABSTRACT FROM AUTHOR]

Since the emergency of coronavirus disease 2019, no specific drug has been developed within the fighting program against its spread. In Cameroon, it has been reported that the dish “yellow soup” can significantly curb the progress of the disease, while no chemical investigations have been done so far to support that conclusion. Chemical investigations of four selected spices of that dish led to the isolation of a total of 44 distinct pure compounds, which were identified using spectroscopic data. Furthermore, the docking scores of the isolated compounds were inspected by AutoDock4.2.6 software toward SARS-CoV-2 multi-targets involving main protease (Mpro), helicase, papain-like protease (PLpro), and human angiotensin‐converting enzyme 2 (ACE2). The most potent isolated compounds underwent molecular dynamics (MD) simulations over 100 ns. Stigmasterol demonstrated outstanding potency toward Mpro and PLpro with ΔG binding values of −35.6 and −36.6 kcal/mol, respectively, compared to nirmatrelvir. Nevertheless, 3β-taraxeryl acetate revealed good binding affinity against helicase and lupeol unveiled superior binding energy toward ACE2 compared to nirmatrelvir. Post-MD analyses manifested great steadiness of the isolated compounds within the binding pockets of SARS-CoV-2 targets throughout 100 ns MD simulations. Stigmasterol, 3β-taraxeryl acetate, and lupeol are recommended for further in vivo/in vitro tests toward SARS-CoV-2 multi-targets.

This study delved into the potential application of Platanus acerifolia leaf extract (PALE) as an environmentally benign corrosion inhibitor. Evaluation of corrosion inhibition was conducted using electrochemical methods, field emission scanning electron microscopy equipped with energy dispersive spectrometer. The results reveal that PALE offers efficient protection for Q235 steel across the temperature range of 298 K–318 K, achieving a maximum corrosion inhibition efficiency of approximately 93%. Furthermore, Density functional theory (DFT) calculations and molecular dynamics (MD) simulations were performed to elucidate the spontaneous and stable adsorption of PALE molecules onto the surface of Q235 steel. This adsorption impedes the diffusion of corrosive substances towards the steel surface, thereby endowing Q235 steel with robust corrosion resistance.

8-oxoguanine (oxoG) is formed in DNA by the action of reactive oxygen species. As a highly mutagenic and the most common oxidative DNA lesion, it is an important marker of oxidative stress. Human 8-oxoguanine-DNA glycosylase (OGG1) is responsible for its prompt removal in human cells. OGG1 is a bifunctional DNA glycosylase with N-glycosylase and AP lyase activities. Aspects of the detailed mechanism underlying the recognition of 8-oxoguanine among numerous intact bases and its subsequent interaction with the enzyme’s active site amino acid residues are still debated. The main objective of our work was to determine the effect (structural and thermodynamic) of introducing an oxoG-clamp in model DNA substrates on the process of 8-oxoG excision by OGG1. Towards that end, we used DNA duplexes modeling OGG1-specific lesions: 8-oxoguanine or an apurinic/apyrimidinic site with either cytidine or the oxoG-clamp in the complementary strand opposite to the lesion. It was revealed that there was neither hydrolysis of the N-glycosidic bond at oxoG nor cleavage of the sugar–phosphate backbone during the reaction between OGG1 and oxoG-clamp-containing duplexes. Possible structural reasons for the absence of OGG1 enzymatic activity were studied via the stopped-flow kinetic approach and molecular dynamics simulations. The base opposite the damage was found to have a critical effect on the formation of the enzyme–substrate complex and the initiation of DNA cleavage. The oxoG-clamp residue prevented the eversion of the oxoG base into the OGG1 active site pocket and impeded the correct convergence of the apurinic/apyrimidinic site of DNA and the attacking nucleophilic group of the enzyme. An obtained three-dimensional model of the OGG1 complex with DNA containing the oxoG-clamp, together with kinetic data, allowed us to clarify the role of the contact of amino acid residues with DNA in the formation of (and rearrangements in) the enzyme–substrate complex.

Introduction: Trypanosoma cruzi is a protozoan parasite that causes the tropical ailment known as Chagas disease, which has its origins in South America. Globally, it has a major impact on health and is transported by insect vector that serves as a parasite. Given the scarcity of vaccines and the limited treatment choices, we conducted a comprehensive investigation of core proteomics to explore a potential reverse vaccine candidate with high antigenicity. Methods: To identify the immunodominant epitopes, T. cruzi core proteomics was initially explored. Consequently, the vaccine sequence was engineered to possess characteristics of non-allergenicity, antigenicity, immunogenicity, and enhanced solubility. After modeling the tertiary structure of the human TLR4 receptor, the binding affinities were assessed employing molecular docking and molecular dynamics simulations (MDS). Results: Docking of the final vaccine design with TLR4 receptors revealed substantial hydrogen bond interactions. A server-based methodology for immunological simulation was developed to forecast the effectiveness against antibodies (IgM + IgG) and interferons (IFN-g). The MDS analysis revealed notable levels of structural compactness and binding stability with average RMSD of 5.03 Aring;, beta-factor 1.09e +5 Å, Rg is 44.7 Aring; and RMSF of 49.50 Aring;. This is followed by binding free energies calculation. The system stability was compromised by the complexes, as evidenced by their corresponding Gibbs free energies of -54.6 kcal/mol. Discussion: Subtractive proteomics approach was applied to determine the antigenic regions of the T cruzi. Our study utilized computational techniques to identify B- and T-cell epitopes in the T. cruzi core proteome. In current study the developed vaccine candidate exhibits immunodominant features. Our findings suggest that formulating a vaccine targeting the causative agent of Chagas disease should be the initial step in its development. [ABSTRACT FROM AUTHOR]

Precise management of the inverse correlation between the total porosity and compressive strength is crucial for the progress of foaming glass–ceramics (FGCs). To deeply understand this relationship, we investigated the atomic-level transformations of five CO2-foaming FGC samples using molecular dynamics simulation. The short-range and intermediate-range structures of the FGCs with varying total porosities (36.68%, 66.28%, 66.96%, 72.21%, and 79.88%) in the system were elucidated. Na cations were observed to exhibit a strong interaction with CO2, accumulating at the surface of the pore wall and influencing the oxygen species. Therefore, the change in the atomic structure of the matrix was accompanied by an increase in the total porosity with an increasing CO2 content. Specifically, as the total porosity increased, the bridging oxygen content within the FGCs rose accordingly. However, once the total porosity exceeded 66.96%, the bridging oxygen content began to decline. This observation was significant considering the role of the bridging oxygen content in forming a continuous cross-linked network of chemical bonds, which contributed to the enhanced mechanical strength. Consequently, the influence of the total porosity on the oxygen species resulted in a two-stage reduction in the compressive strength. This study offers valuable insights for the development of high-strength lightweight FGCs. [ABSTRACT FROM AUTHOR]

Phosphoglycerate kinase-1 (PGK1) is an enzyme found in the cells and tissues of the human body. Deficiency of this enzyme leads to deadly neurodegenerative diseases, such as stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease and apoptosis. Since there is no ideal drug candidate to cure such diseases by activating this enzyme, this study aimed to discover a new potent candidate from cyanobacteria using in silico pharmacological applications. The preparation of both the protein and the ligands was performed in Maestro 13.2, followed by docking using a range of modules, including Prepwizard, Ligprep, Sitemap, Glidgrid and Glide Dock, with different modes, such as HTVS, SP, XP and Desmond v6.8. Among the 240 docked cyanobacterial metabolites, lyngbyastatin, hoiamide D, lyngbyastatin 4, lyngbyastatin I, lyngbyastatin 7, tigicamide A, hoiamide and symlocamid A, showed remarkable docking and energy values. These compounds exhibit better potency as promising drugs at the target residues than reference molecules, as evidenced by better docking scores, energies, lower root mean square deviation (RMSD) with stronger binding affinities in molecular docking and MD simulations. The study demonstrated that these compounds are the first to be identified as triggers of PGK1, and it was anticipated that these metabolites would show beneficial effects when tested in both in vitro and in vivo studies of such deadly neurodegenerative diseases. The results obtained in the study suggested that these metabolites may provide a beneficial drug effect to reduce the complications associated with PGK1. The current work is aimed to identify a potent candidate in treating neurodegenerative diseases caused by phosphoglycerate kinase 1 (PGK1) dysfunction. Hence, 240 secondary metabolites identified/isolated from the various cyanobacterial species were selected based on their prevailing pharmacological properties. Eventually, lyngbyastatin (a cyclic depsipeptide) was known to be an effective candidate for neurogenerative diseases, revealing better stability even than the standard drug terazosin. Based on the findings, the present study proposes that it could act as an effective neuroprotective agent and further clinical studies are suggested to validates its efficacy. [ABSTRACT FROM AUTHOR]

Hydrogen cyanide (HCN) gas, a major industrial pollution, is generated as a result of burning fossil fuels and indirectly contributes to the greenhouse effect. Therefore, deep eutectic solvents (DES) can provide a low-cost and effective method for its detection and removal. Density function theory (DFT) computations have been used to conduct a theoretical investigation of a DES, composed of choline chloride (ChCl) and 1,3-propanediol (PD). The potential of DES for HCN adsorption or binding has been examined using computational calculations. Herein, the viability of adsorption of HCN by the DES composed of ChCl and PD in 1:1 and 1:2 ratio, that is, 2a and 3a have been studied and further, the number of HCN molecules have been varied. The study was conducted by analysing the interactions and electronic properties obtained from DFT computations. Density of states (DOS) spectra were determined and used to examine the stability of the complex formed between DES and HCN. Significant interactions between DES systems and HCN molecules have been observed. Natural bond orbital (NBO) analysis indicated an increase in the strength of interactions upon an increase in PD molecules. Molecular dynamics (MD) simulations of the DESs with and without HCN were performed and investigated. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) trajectories were extracted and used to analyse the interactions in DES and HCN at different ratios. The RMSD plots showed increased values with lower fluctuations with an increase in the number of HCN molecules, demonstrating that the structures remained in equilibrium despite the rise in the number of HCN molecules. RMSD patterns revealed the stability of the complex formed between DES and HCN molecules. RMSF plot indicated the stable geometries obtained upon interacting DES with HCN molecules. The number of hydrogen bonds increased with an increase in the number of DES molecules. [ABSTRACT FROM AUTHOR]

The global prevalence of obesity-related systemic disorders, including non-alcoholic fatty liver disease (NAFLD), and cancers are rapidly rising. Several of these disorders involve peroxisome proliferator-activated receptors (PPARs) as one of the key cell signaling pathways. PPARs are nuclear receptors that play a central role in lipid metabolism and glucose homeostasis. They can activate or suppress the genes responsible for inflammation, adipogenesis, and energy balance, making them promising therapeutic targets for treating metabolic disorders. In this study, an attempt has been made to screen novel PPAR pan-agonists from the ZINC database targeting the three PPAR family of receptors (α, γ, β/δ), using molecular docking and molecular dynamics (MD) simulations. The top scoring five ligands with strong binding affinity against all the three PPAR isoforms were eprosartan, canagliflozin, pralatrexate, sacubitril, olaparib. The ADMET analysis was performed to assess the pharmacokinetic profile of the top 5 molecules. On the basis of ADMET analysis, the top ligand was subjected to MD simulations, and compared with lanifibranor (reference PPAR pan-agonist). Comparatively, the top-scoring ligand showed better protein–ligand complex (PLC) stability with all the PPARs (α, γ, β/δ). When experimentally tested in in vitro cell culture model of NAFLD, eprosartan showed dose dependent decrease in lipid accumulation and oxidative damage. These outcomes suggest potential PPAR pan-agonist molecules for further experimental validation and pharmacological development, towards treatment of PPAR-mediated metabolic disorders. [ABSTRACT FROM AUTHOR]

Hepatitis is a medical condition characterized by inflammation of the liver. It is commonly caused by the hepatitis viruses A, B, C, D, and E. Hepatitis A virus (HAV) is highly contagious and can spread from infected individuals, through contaminated food, blood, or can also be water-borne. As per the statistics of World Health Organization (WHO), HAV infects about 1.4 million individuals each year globally. In this research work, we have focused on identifying natural product-based potential inhibitors for the two major enzymes of HAV namely 3C proteinase (3Cpro) and RNA-directed RNA polymerase (RdRP). The enzyme 3Cpro plays an important role in proteolytic activity that promotes viral maturation and infectivity. RNA-directed RNA polymerase facilitate viral replication and transcription. Structure-based virtual screening was carried out using NPACT database that contains a collection of 1574 curated plant-derived natural compounds that are validated by experiments. The screening procedure identified the phytochemical Mulberrofuran W, which could bind to both the targets 3Cpro and RdRP. The phytochemical Mulberrofuran W also had better binding affinity compared to the control compounds atropine and pyridinyl ester, which are previously identified inhibitors of HAV 3Cpro and RdRP, respectively. The Mulberrofuran W bound 3Cpro and RdRP complexes were subjected to 200 ns molecular dynamics simulations and were found to be stable and interacting with the active site of the enzymes throughout the course of complex MD simulations. In addition to DFT, MMGBSA studies were also performed to validate the identified potential inhibitor further. The identified phytochemical Mulberrofuran W can be considered as a new potential drug candidate and could be taken up for experimental evaluation against HAV infection. [ABSTRACT FROM AUTHOR]

Single-point mutations in the Kirsten rat sarcoma (KRAS) viral proto-oncogene are the most common cause of human cancer. In humans, oncogenic KRAS mutations are responsible for about 30% of lung, pancreatic, and colon cancers. One of the predominant mutant KRAS G12D variants is responsible for pancreatic cancer and is an attractive drug target. At the time of writing, no Food and Drug Administration (FDA) approved drugs are available for the KRAS G12D mutant. So, there is a need to develop an effective drug for KRAS G12D. The process of finding new drugs is expensive and time-consuming. On the other hand, in silico drug designing methodologies are cost-effective and less time-consuming. Herein, we employed machine learning algorithms such as K-nearest neighbor (KNN), support vector machine (SVM), and random forest (RF) for the identification of new inhibitors against the KRAS G12D mutant. A total of 82 hits were predicted as active against the KRAS G12D mutant. The active hits were docked into the active site of the KRAS G12D mutant. Furthermore, to evaluate the stability of the compounds with a good docking score, the top two complexes and the standard complex (MRTX-1133) were subjected to 200 ns MD simulation. The top two hits revealed high stability as compared to the standard compound. The binding energy of the top two hits was good as compared to the standard compound. Our identified hits have the potential to inhibit the KRAS G12D mutation and can help combat cancer. To the best of our knowledge, this is the first study in which machine-learning-based virtual screening, molecular docking, and molecular dynamics simulation were carried out for the identification of new promising inhibitors for the KRAS G12D mutant. [ABSTRACT FROM AUTHOR]

The interaction of heparin with antithrombin (AT) involves a specific sequence corresponding to the pentasaccharide GlcNAc/NS6S-GlcA-GlcNS3S6S-IdoA2S-GlcNS6S (AGA*IA). Recent studies have revealed that two AGA*IA-containing hexasaccharides, which differ in the sulfation degree of the iduronic acid unit, exhibit similar binding to AT, albeit with different affinities. However, the lack of experimental data concerning the molecular contacts between these ligands and the amino acids within the protein-binding site prevents a detailed description of the complexes. Differential epitope mapping (DEEP)-STD NMR, in combination with MD simulations, enables the experimental observation and comparison of two heparin pentasaccharides interacting with AT, revealing slightly different bound orientations and distinct affinities of both glycans for AT. We demonstrate the effectiveness of the differential solvent DEEP-STD NMR approach in determining the presence of polar residues in the recognition sites of glycosaminoglycan-binding proteins. [ABSTRACT FROM AUTHOR]

Context: Human estrogen-related receptor γ (hERRγ) is a key protein involved in various endocrines and metabolic signaling. Numerous environmental endocrine-disrupting chemicals (EDCs) can impact related physiological activities through receptor signaling pathways. Focused on hERRγ with 4-isopropylphenol, bisphenol-F (BPF), and BP(2,2)(Un) complexes, we executed molecular docking and multiple molecular dynamics (MD) simulations along with molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) and solvation interaction energy (SIE) calculation to study the detailed dynamical structural characteristics and interactions between them. Molecular docking showed that hydrogen bonds and hydrophobic interactions were the prime interactions to keep the stability of BPF-hERRγ and hERRγ-BP(2,2)(Un) complexes. Through MD simulations, we observed that all complexes reach equilibrium during the initial 50 ns of simulation, but these three EDCs lead to local structure changes in hERRγ. Energy results further identified key residues L268, V313, L345, and F435 around the binding pockets through CH-π, π-π, and hydrogen bonds interactions play an important stabilizing role in the recognition with EDCs. And most noticeable of all, hydrophobic methoxide groups in BP(2,2)(Un) is useful for decreasing the binding ability between EDCs and hERRγ. These results may contribute to evaluate latent diseases associated with EDCs exposure at the micro level and find potential substitutes. Method: Autodock4.2 was used to conduct the molecular docking, sietraj program was performed to calculate the energy, and VMD software was used to visualize the structure. Amber18 was conducted to perform the MD simulation and other analyses. [ABSTRACT FROM AUTHOR]

Nitrobenzene derivatives present an environmental concern to aquatic organisms, as well as a potential adverse effects on human health due to their toxicity. Therefore, monitoring nitrobenzene contamination levels is critical to protect both the ecosystem and the public. This study aims to quantitatively correlate the toxicity of nitrobenzene derivatives to their chemical structures using computational chemistry methods such as 3D‐QSPR, HQSPR, Molecular Docking and MD simulation. Additionally, to investigate the type of interactions and stability of nitrobenzene derivatives with the PP2 protein involved in the Phloem protein 2 (PP2). From each computational method a prediction model was extracted HQSPR (Atomic, Bonds, Donor/Acceptor, 3D‐QSPR (Steric, Electrostatic, Hydrophobic, Acceptor), and used for the design of X1 and X2 new nitrobenzene derivatives, which showed remarkable stability and better interactions. This study contributes to the understanding of the nitrobenzene derivatives' toxicity and offers materials towards the understanding of the mechanism of action of these substances in protein–ligand interactions. [ABSTRACT FROM AUTHOR]

AKR1B1 and AKR1B10 are important members of aldo–keto reductase family which plays a significant role in cancer progression by modulating cellular metabolism. These enzymes are involved in various metabolic processes, including the synthesis and metabolism of hormones, detoxification of reactive aldehydes, and the reduction of various endogenous and exogenous compounds. This study aimed to explore the potential of strychnine as an anticancer agent by targeting AKR1B1 and AKR1B10 via drug repurposing approach. To assess the drug-like properties of strychnine, a physiologically based pharmacokinetic (PKPB) model and High Throughput Pharmacokinetics (HTPK) approach were employed. The obtained results fell within the expected range for drug molecules, confirming its suitability for further investigation. Additionally, density functional theory (DFT) studies were conducted to gain insight into the electronic properties contributing to the drug molecule's reactivity. Building upon the promising DFT results, molecular docking analysis using the AutoDock tool was performed to examine the binding interactions between strychnine and the proposed targets, AKR1B1 and AKR1B10. Findings from the molecular docking studies suggested a higher probability of strychnine acting as an inhibitor of AKR1B1 and AKR1B10 with docking scores of − 30.84 and − 29.36 kJ/mol respectively. To validate the stability of the protein–ligand complex, Molecular Dynamic Simulation (MDS) studies were conducted, revealing the formation of a stable complex between the enzymes and strychnine. This comprehensive approach sheds light on the potential effectiveness of strychnine as a treatment for breast, lung, liver, and pancreatic cancers, as well as related malignancies. The novel insights gained from the physiologically based pharmacokinetic modeling, density functional theory, molecular docking, and molecular dynamics simulations collectively support the prospect of strychnine as a promising molecule for anticancer therapy. Further investigations are warranted to validate these findings and explore the therapeutic potential of strychnine in preclinical and clinical settings. [ABSTRACT FROM AUTHOR]

Discoidin domain receptor 1 (DDR1) kinase has emerged as a promising target for cancer therapy, and selective DDR1 inhibitors have shown promise as effective therapeutic candidates. Herein, we have identified the first coumarin-based selective DDR1 inhibitors via repurposing of a recent series of carbonic anhydrase inhibitors. Among these, ureidocoumarins 3a, 3i, and 3q showed the best DDR1 inhibitory activities. The m-trifluoromethoxy phenyl member 3q potently inhibited DDR1 with an IC50 of 191 nM, while it showed less inhibitory activity against DDR2 (IC50 = 5080 nM). 3q also exhibited favorable selectivity in a screening platform with 23 common off-target kinases, including BCR-ABL. In the cellular context, 3q showed moderate antiproliferative effects, while 3i, with the third rank in DDR1 inhibition, exerted the best anticancer activity with sub-micromolar GI50 values over certain DDR1-dependent cell lines. Molecular docking and MD simulations disclosed the putative binding mode of this coumarin chemotype and provided insights for further optimization of this scaffold. The present findings collectively supported the potential improvement of ureidocoumarins 3i and 3q for cancer treatment. [ABSTRACT FROM AUTHOR]

Understanding and characterizing semi-crystalline models with crystalline and amorphous segments is crucial for industrial applications. A coarse-grained molecular dynamics (CGMD) simulations study probed the crystal network formation in high-density polyethylene (HDPE) from melt, and shed light on tensile properties for microstructure analysis. Modified Paul–Yoon–Smith (PYS/R) forcefield parameters are used to compute the interatomic forces among the PE chains. The isothermal crystallization at 300 K and 1 atm predicts the multi-nucleus crystal growth; moreover, the lamellar crystal stems and amorphous region are alternatively oriented. A one-dimensional density distribution along the alternative lamellar stems further confirms the ordering of the lamellar-stack orientation. Using this plastic model preparation approach, the semi-crystalline model density ( ρ c r ) of ca. 0.913 g·cm−3 and amorphous model density ( ρ a m ) of ca. 0.856 g·cm−3 are obtained. Furthermore, the ratio of ρ c r / ρ a m ≈ 1.06 is in good agreement with computational (≈1.096) and experimental (≈1.14) data, ensuring the reliability of the simulations. The degree of crystallinity ( χ c ) of the model is ca. 52% at 300 K. Nevertheless, there is a gradual increase in crystallinity over the specified time, indicating the alignment of the lamellar stems during crystallization. The characteristic stress–strain curve mimicking tensile tests along the z-axis orientation exhibits a reversible sharp elastic regime, tensile strength at yield ca. 100 MPa, and a non-reversible tensile strength at break of 350%. The cavitation mechanism embraces the alignment of lamellar stems along the deformation axis. The study highlights an explanatory model of crystal network formation for the PE model using a PYS/R forcefield, and it produces a microstructure with ordered lamellar and amorphous segments with robust mechanical properties, which aids in predicting the microstructure–mechanical property relationships in plastics under applied forces. [ABSTRACT FROM AUTHOR]

Objectives: In our continuous efforts to combat COVID-19, our objective was to conduct a comprehensive computer-aided drug design study utilizing 4924 African natural metabolites sourced from diverse databases across various African regions from 1962 to 2019. The primary goal was to target the SARS-CoV-2 helicase, a crucial enzyme in viral replication. Methods: We employed structural fingerprint and molecular similarity studies with VXG, the co-crystallized ligand, as a reference. Subsequently, docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were conducted. Results: The structural fingerprint analysis identified 200 structurally similar compounds, then the molecular similarity studies selected 40 compounds. Among them, 15 metabolites with low free energies, favorable binding modes, and promising ADMET properties were identified. Four compounds were excluded according to the toxicity studies. Compound 1552, 1-((S)-2,3-dihydro-2-((R)-1-hydroxypropan-2-yl)benzofuran-5-yl)ethenone, exhibited the most favorable docking results. Molecular dynamics simulations conclusively demonstrated its stable binding to the SARS-CoV-2 helicase, characterized by low energy and optimal dynamics. Conclusion: The findings suggest promising avenues for potential COVID-19 cures, encouraging further exploration through in vitro and in vivo studies of the identified compounds, particularly compound 1552. [ABSTRACT FROM AUTHOR]

Disparity in the activity of Endoplasmic reticulum (ER) leads to degenerative diseases, mainly associated with protein misfolding and aggregation leading to cellular dysfunction and damage, ultimately contributing to ER stress. ER stress activates the complex network of Unfolded Protein Response (UPR) signaling pathways mediated by transmembrane proteins IRE1, ATF6, and PERK. In addition to UPR, many ER chaperones have evolved to optimize the output of properly folded secretory and membrane proteins. Glucose-regulated protein 94 (GRP94), an ER chaperone of heat shock protein HSP90 family, directs protein folding through interaction with other components of the ER protein folding machinery and assists in ER-associated degradation (ERAD). Activation of GRP94 would increase the efficacy of protein folding machinery and regulate the UPR pathway toward homeostasis. The present study aims to screen for novel agonists for GRP94 based on Core hopping, pharmacophore hypothesis, 3D-QSAR, and virtual screening with small-molecule compound libraries in order to improve the efficiency of native protein folding by enhancing GRP94 chaperone activity, therefore to reduce protein misfolding and aggregation. In this study, we have employed the strategy of small molecule-dependent ER programming to enhance the chaperone activity of GRP94 through scaffold hopping-based screening approach to identify specific GRP94 agonists. New scaffolds generated by altering the cores of NECA, the known GRP94 agonist, were validated by employing pharmacophore hypothesis testing, 3D-QSAR modeling, and molecular dynamics simulations. This facilitated the identification of small molecules to improve the efficiency of native protein folding by enhancing GRP94 activity. High-throughput virtual screening of the selected pharmacophore hypothesis against Selleckchem and ZINC databases retrieved a total of 2,27,081 compounds. Further analysis on docking and ADMET properties revealed Epimedin A, Narcissoside, Eriocitrin 1,2,3,4,6-O-Pentagalloylglucose, Secoisolariciresinol diglucoside, ZINC92952357, ZINC67650204, and ZINC72457930 as potential lead molecules. The stability and interaction of these small molecules were far better than the known agonist, NECA indicating their efficacy in selectively alleviating ER stress-associated pathogenesis. These results substantiate the fact that small molecule-dependent ER reprogramming would activate the ER chaperones and therefore reduce the protein misfolding as well as aggregation associated with ER stress in order to restore cellular homeostasis. [ABSTRACT FROM AUTHOR]

Remdesivir, a C-nucleotide prodrug binds to the viral RNA-dependent-RNA polymerase (RdRp) and inhibits the viral replication by terminating RNA transcription prematurely. It is reported in literature that interaction between the C-1’β–CN moiety of Remdesivir (RDV) and the Ser861 residue in RdRp enzyme, causes a delayed chain termination during the RNA replication process and is one of the important aspect of its mechanism of action. In the pursuance of increasing the biological activity of RDV and enhancing the SAR studies, against RNA viruses, we have designed its fourteen C1’β substituted analogs, 10 –23 bearing 4/5-membered heterocyclic rings. The docking and 100 ns molecular dynamics (MD) simulations of 10-23 to the RdRp protein (PDB ID: 7L1F) revealed important interactions between 2’,3’-diol, oxo group of phosphoramidate, nitrogen residues of heterocyclic rings of synthetic molecules with Arg555, Arg553, Ser759, Cys622, Asn691, Asp623 amino acid residues of protein. The docking score of 2-ethylbutyl ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(1H-1,2,3-triazol-4-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate, 11 was found to be the higher than RDV among 14 new compounds i.e. -5.20 kcal/mol. Out of 3 compounds, 10, 12 and 13 submitted for MD simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis, trifluoro-oxadiazole derivative, 13 showed higher binding energy as compared to Remdesivir. The predicted ADMET properties of 14 compounds showed their potential for being drug candidates. The present study suggests that substitution at the C1’β position by 4/5-membered rings plays an important role in the interactions between nucleoside/tide and target protein.

Abstract Background Breast cancer, a leading cause of female mortality, is closely linked to mutations in estrogen receptor beta (ESR2), particularly in the ligand‐binding domain, which contributed to altered signaling pathways and uncontrolled cell growth. Objectives/Aims This study investigates the molecular and structural aspects of ESR2 mutant proteins to identify shared pharmacophoric regions of ESR2 mutant proteins and potential therapeutic targets aligned within the pharmacophore model. Methods This study was initiated by establishing a common pharmacophore model among three mutant ESR2 proteins (PDB ID: 2FSZ, 7XVZ, and 7XWR). The generated shared feature pharmacophore (SFP) includes four primary binding interactions: Hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), hydrophobic interactions (HPho), and Aromatic interactions (Ar), along with halogen bond donors (XBD) and totalling 11 features (HBD: 2, HBA: 3, HPho: 3, Ar: 2, XBD: 1). By employing an in‐house Python script, these 11 features distributed into 336 combinations, which were used as query to isolate a drug library of 41,248 compounds and subjected to virtual screening through the generated SFP. Results The virtual screening demonstrated 33 hits showing potential pharmacophoric fit scores and low RMSD value. The top four compounds: ZINC94272748, ZINC79046938, ZINC05925939, and ZINC59928516 showed a fit score of more than 86% and satisfied the Lipinski rule of five. These four compounds and a control underwent molecular (XP Glide mode) docking analysis against wild‐type ESR2 protein (PDB ID: 1QKM), resulting in binding affinity of −8.26, −5.73, −10.80, and −8.42 kcal/mol, respectively, along with the control −7.2 kcal/mol. Furthermore, the stability of the selected candidates was determined through molecular dynamics (MD) simulations of 200 ns and MM‐GBSA analysis. Conclusion Based on MD simulations and MM‐GBSA analysis, our study identified ZINC05925939 as a promising ESR2 inhibitor among the top four hits. However, it is essential to conduct further wet lab evaluation to assess its efficacy.

This study aimed to look at how lignin sulfonate (LS) inhibited corrosion of mild steel (MS) in a 1.0 M NaCl solution. Gravimetric and Electrochemical techniques were used to acquire a thorough grasp of the inhibitory effects of LS on MS corrosion. In addition, the current work used computational approaches to investigate, this connection that exists between the inhibitor compounds' functional features and their adsorption capabilities on the MS surface. Weight loss, Potentiodynamic polarization (PDP), and open-circuit studies demonstrated moderate anticorrosion properties of the investigated chemicals. Results showed that LS had the best inhibition performance, reaching 51.6% at a concentration of 0.02×10−2MLS. The polarization approach (PDP) revealed that the intended substances were mixed-type inhibitors, which prevented concurrent processes involving anodes and cathodes. In addition, the interaction pattern between the LS and MS surfaces matched, with physical interactions aiding the adsorption mechanisms of both chemicals. Furthermore, the stability of LS under several operating conditions temperature influence and submerge duration on inhibitory effectiveness were investigated. Additionally, the data fit well with both the Langmuir and El-Awady adsorption models. Molecular Dynamics (MD) and Density Functional Theory (DFT) investigations agree with those obtained through experimental methods, confirming the anticorrosion activity of the LS under investigation. Gibbs free energy value (≤−26 kJmol-1) confirms spontaneity and mainly the physical nature of the adsorption, also the mechanism of inhibition is discussed. Surface morphology indicates the formation of the LS barrier on MS.

Pregnane X receptor (PXR) is a heterologous biosensor that is involved in the metabolic pathway of environmental pollutants, regulating the transcription of genes involved in biotransformation. There are significant differences in the selectivity and specificity of organic pollutants (OPs) toward polar bear PXR (pbPXR) and human PXR (hPXR), but the detailed dynamical characteristics of their interactions are unclear. Homology Modeling, molecular docking, molecular dynamics simulation, and free energy calculation were used to analyze the recognition of pbPXR and hPXR by three OPs: BPA, chlordane and toxaphene. Comparing interaction patterns along with binding free energy of pbPXR and hPXR with these three OPs revealed that although pbPXR and hPXR interact similar with these three OPs, these OPs have different effects on the internal dynamics of pbPXR and hPXR. This results in significant alterations in the interaction of key residues near Leu209, Met243, Phe288, Met323, and His407 with OPs, thereby influencing their binding energy. Non-polar interactions, especially van der Waals interactions, were found to be the dominating factors in interacting of these OPs with PXRs. The region surrounding these key residues facilitates hydrophobic contacts with PXR, which are crucial for the selective activation of PXRs in different species by these three OPs. These findings are of significant guidance in understanding the impacts of environmental endocrine disruptors on different organisms.

Interleukin-8 (IL-8) is a chemokine, a type of signaling molecule that has a role in immunological responses and inflammation. In recent years, IL-8 is additionally related to cancer growth and recurrence. Breast cancer growth, progression, and metastatic development are all linked to IL-8. Breast cancer cells are known to develop faster when IL-8 stimulates their proliferation and survival. It can also cause angiogenesis, or the creation of new blood vessels, which is necessary for tumor nutrition and growth. IL-8 and curcumin have been subjects of interest in drug design, particularly in the context of inflammation-related disorders and cancer. This study aims to give an overview of the role of IL-8. Inhibitor-based treatment approaches were being used to target IL-8 with curcumin. Molecular docking method was employed to find a potential interaction to supress competitive inhibition of IL-8 with curcumin. PASS analysis and ADMET characteristics were also being carried out. In the end, IL-8 complexed with curcumin is chosen for MD simulations. Overall, our results showed that during the simulation, the complex stayed comparatively stable. It is also possible to investigate curcumin further as a possible treatment option. The combined results imply that IL-8 and their genetic alterations can be studied in precision cancer therapeutic treatments, utilizing target-driven therapy and early diagnosis.

Abstract In the current study, Azo-Thiohydantoins derivatives were synthesized and characterized by using various spectroscopic techniques including FTIR, 1H-NMR, 13C-NMR, elemental and HRMS analysis. The compounds were evaluated for alkaline phosphatase activity and it was observed that among all the synthesized compounds, derivative 7e exhibited substantial inhibitory activity (IC50 = 0.308 ± 0.065 µM), surpassing the standard inhibitor (L–Phenyl alanine, IC50 = 80.2 ± 1.1 µM). Along with this, these derivatives were comprehensively examined regarding the electronic properties and reactivity of the synthesized compounds using Density Functional Theory (DFT) calculations, where the results were found very promising and the synthesized compound were found stable. After that, SwissADME evaluations highlighted compounds for their favorable physicochemical properties, including solubility and drug-likeness. Molecular docking exhibited the strong binding affinities of 7f and 7e derivatives with intestinal alkaline phosphatase (IAP), further supported by Molecular Dynamics (MD) simulations. This comprehensive integration of experimental and computational approaches sheds the light on the potential therapeutic applications of the synthesized compounds. By providing a detailed investigation of these aspects, this research opens the avenues for the development of novel pharmacologically active compounds with diverse applications.

Grain boundaries (GBs) play a crucial role on the structural stability and mechanical properties of Cu and its alloys. In this work, molecular dynamics (MD) simulations are employed to study the effects of Fe solutes on the formation energy, excess volume, dislocations and melting behaviors of GBs in CuFe alloys. It is illustrated that Fe solute affects the structural stability of Cu GBs substantially, the formation energy of GBs is reduced, but the thickness and melting point of GBs are increased, that is, the structural stability of Cu GBs is significantly improved owing to the Fe solutes. A strong scaling law exists between the formation energy, excess volume, thickness and melting point of GBs. Therefore, Fe solid solute plays an important role in the characteristics of GBs in bi-crystal Cu.

Abstract Respiratory viral infections, a major public health concern, necessitate continuous development of novel antiviral strategies, particularly in the face of emerging and re-emerging pathogens. In this study, we explored the potential of human milk oligosaccharides (HMOs) as broad-spectrum antiviral agents against key respiratory viruses. By examining the structural mimicry of host cell receptors and their known biological functions, including antiviral activities, we assessed the ability of HMOs to bind and potentially inhibit viral proteins crucial for host cell entry. Our in silico analysis focused on viral proteins integral to host-virus interactions, namely the hemagglutinin protein of influenza, fusion proteins of respiratory syncytial and human metapneumovirus, and the spike protein of SARS-CoV-2. Using molecular docking and simulation studies, we demonstrated that HMOs exhibit varying binding affinities to these viral proteins, suggesting their potential as viral entry inhibitors. This study identified several HMOs with promising binding profiles, highlighting their potential in antiviral drug development. This research provides a foundation for utilizing HMOs as a natural source for designing new therapeutics, offering a novel approach in the fight against respiratory viral infections.