The quantum chemical calculations, based on density functional theory, have been implemented to explore the corrosion inhibition mechanism and the corresponding inhibition effectiveness of ...quinazolinone and pyrimidinone compounds, viz., 6-chloroquinazolin-4(3H)-one (Q1A); 2,3-dihydro-3-phenethyl-2-thioxopyrido2,3-dpyrimidin-4(1H)-one (Q1B) and 6-chloro-2,3-dihydro-3-phenethyl-2-thioxoquinazolin-4(1H)-one (Q1C) for mild steel in acidic solution. Global reactivity of the molecules related to the quantum chemical parameters such as EHOMO, ELUMO, energy gap (ΔE), softness (S), hardness (η) and fraction of electron transferred (ΔN) between the inhibitor molecule and the metal surface atom have been calculated and explored. In order to describe the reactive sites of the inhibitor molecules Fukui indices analysis has been performed. To mimic the real environment of corrosion inhibition, molecular dynamic (MD) simulations have also been modelled consisting of all concerned species (inhibitor molecule, H2O, H3O+ ion, SO42− ion and Fe surface) and thereby simulated by the consistent-valence force field (CVFF).
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•Corrosion inhibition performance of quinazolinone and pyrimidinone compounds is theoretically investigated.•DFT reveals the active participation of heterocyclic moieties and CO, CS, Cl substituent groups in adsorption process.•In order to get better insightfulness MD simulations have been carried out in presence of H2O, H3O+, SO42– and Fe surfaces.•MD simulations unveil the adsorption process of heterocyclic ring, CH2CH2 group and benzene ring of the inhibitors.•Binding ability of quinazolinone and pyrimidinone compounds follow the order of Q1C>Q1B>Q1A.
The stacking fashion of two-dimensional material system plays critical roles on their multi-functional properties. In this study, bilayer graphene with or without pre-crack was rotated by different ...angles and tensile mechanical properties of bilayer graphene were investigated by molecular dynamics simulations. It was found that the fracture strength, Young's modulus and fracture toughness of bilayer graphene are highly dependent on the rotation angle and reach maximum values when θbottom = θupper = 0°. And as for bilayer graphene without pre-crack, the mechanical properties of each layer dominate the mechanical behaviors of bilayer graphene. However, when pre-crack exists, fracture is mainly caused by super high stress concentration and the propagation of crack in bilayer graphene is blocked due to the existence of rotation angles to some extent. On the other hand, a continuum laminate-plate model was developed, which could efficiently predict the mechanical properties of bilayer graphene with or without pre-crack under different rotation angles. This work provided an in-depth understanding on the mechanical characteristics of bilayer graphene and laid foundation for the structural designs of advanced graphene-based nanomaterials.
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•Mechanical properties of bilayer graphene are highly dependent on the rotation angle.•The mechanics of each layer dominates the mechanical behaviors of bilayer graphene.•A continuum laminate-plate model could efficiently predict the mechanics of bilayer graphene.
7H-Dibenzoc,gcarbazole (DBC) is a prevalent environmental contaminant that induces tumorigenesis in several experimental animals. Recently, it has been utilized to develop high-performance solar ...cells and organic phosphorescent materials. It is imperative to strengthen investigations of DBC metabolism to understand its potential risks to human health. In this study, human CYP1A1 was employed as the metabolic enzyme to investigate the metabolic mechanism of DBC by molecular docking, molecular dynamics (MD) simulation, and quantum mechanical (QM) calculation. The results indicate that DBC binds to CYP1A1 in two modes (mode 1 and mode 2) mainly through nonpolar solvation energies (ΔGnonpolar). The formation of the two binding modes is attributed to the anchoring effect of the hydrogen bond formed by DBC with Asp320 (mode 1) or Ser116 (mode 2). Mode 1 is a "reactive" conformation, while mode 2 is not considered a "reactive" conformation. C5 is identified as the dominant site, and the pyrrole nitrogen cannot participate in the metabolism. DBC is metabolized mainly by a distinct electrophilic addition-rearrangement mechanism, with an energy barrier of 21.74 kcal/mol. The results provide meaningful insights into the biometabolic process of DBC and contribute to understanding its environmental effects and health risks.
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•DBC has two binding modes in the CYP1A1 active site.•C5 is the dominant site of DBC metabolism in CYP1A1.•The enzyme environment promotes the electrophilic reaction at the C5 site.•DBC is metabolized in CYP1A1 mainly by the distinct electrophilic addition mechanism.
•T-1-MMPA was designed according to the essential pharmacophoric characteristics EGFR inhibitors.•T-1-MMPA potential to inhibit EGFR was indicated by DFT, Docking, MD, MM-GPSA, PLIP, ED, and ...ADMET.•In vitro studies showed that T-1-MMPA was effective against MDA-MB-231 and other three cancer cell lines.•T-1-MMPA prevented MDA-MB-231 haling, arrested its growth at the s phase, induced apoptosis, and decreased BCL2 and MMP7 gene expression.•T-1-MMPA’s hepatic safety was further corroborated through in vivo investigation.
A new EGFR inhibitor has been developed from theobromine (meta methoxy phenyl)acetamide derivative), T-1-MMPA, exhibited the essential pharmacophoric characteristics needed to bind toEGFR's pocket. T-1-MMPA's anticancer potential was first estimated through various structure-based computational studies (DFT, docking, MD simulations over 200 ns, MM-GPSA, PLIP, ED, bi-dimensional and ADMET), which revealed that T-1-MMPA effectively bound to and inhibited the EGFR protein. The ADME and toxicity profiles of T-1-MMPA were also predicted computationally before the semi synthesis, and a high degree of drug-likeness was indicated. Then, T-1-MMPA (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(3-methoxyphenyl)acetamide) was prepared to scrutinize the obtained in silico results. Subsequent in vitro studies showed that T-1-MMPA was effective against MDA-MB-231cell lines (triple-negative breast cancer), with an IC50 value of 1.42 µM, compared to the reference drug (0.92 µM) and exhibited a higher selectivity index of 1.9. Interestingly, T-1-MMPA also inhibited the growth of other three cancer cell lines (A549, CaCO-2, and HepG-2) with IC50 values of 1.57, 1.76, and 2.53 µM, respectively. Additionally, T-1-MMPA effectively prevented the healing and migration abilities of the MDA-MB-231 cell lines, arrested the cell growth at the S phase and induced apoptosis, as confirmed by AO/EB staining assay as well as the flow cytometry. Moreover, T-1-MMPA caused down-regulation of the BCL2 and MMP7 gene expression in the treated MDA-MB-231 cells. Finally, as the computational findings indicated T-1-MMPA’s hepatic safety, it was further corroborated through in vivo investigation.
The evolution of the SARS‐CoV‐2 new variants reported to be 70% more contagious than the earlier one is now spreading fast worldwide. There is an instant need to discover how the new variants ...interact with the host receptor (ACE2). Among the reported mutations in the Spike glycoprotein of the new variants, three are specific to the receptor‐binding domain (RBD) and required insightful scrutiny for new therapeutic options. These structural evolutions in the RBD domain may impart a critical role to the unique pathogenicity of the SARS‐CoV‐2 new variants. Herein, using structural and biophysical approaches, we explored that the specific mutations in the UK (N501Y), South African (K417N‐E484K‐N501Y), Brazilian (K417T‐E484K‐N501Y), and hypothetical (N501Y‐E484K) variants alter the binding affinity, create new inter‐protein contacts and changes the internal structural dynamics thereby increases the binding and eventually the infectivity. Our investigation highlighted that the South African (K417N‐E484K‐N501Y), Brazilian (K417T‐E484K‐N501Y) variants are more lethal than the UK variant (N501Y). The behavior of the wild type and N501Y is comparable. Free energy calculations further confirmed that increased binding of the spike RBD to the ACE2 is mainly due to the electrostatic contribution. Further, we find that the unusual virulence of this virus is potentially the consequence of Darwinian selection‐driven epistasis in protein evolution. The triple mutants (South African and Brazilian) may pose a serious threat to the efficacy of the already developed vaccine. Our analysis would help to understand the binding and structural dynamics of the new mutations in the RBD domain of the Spike protein and demand further investigation in in vitro and in vivo models to design potential therapeutics against the new variants.
This study precisely explored the mechanism of the interaction of the spike RBD with the host ACE2 and revealed the differences in the binding of the reference and new variants. The systematic investigation revealed that the South African and Brazilian variants are more lethal than the others due to inter‐protein contacts specifically the electrostatic while the N501Y is comparable with the wild type. We hypothesized that the residue at 501Y is continuously subjected to positive selection pressure. We further demonstrated the dynamic behavior is also changed with the protein evolution. Conclusively, this study provides strong basis for structure and rationale‐based drug designing against the new variant by exploring the noticeable differences.
Viscosin is a membrane-permeabilizing, cyclic lipopeptide (CLiP) produced by Pseudomonas species. Here, we have studied four synthetic analogs (L1W, V4W, L5W, L7W), each with one leucine (Leu; L) or ...valine residue exchanged for tryptophan (Trp; W) by means of time-resolved fluorescence spectroscopy of Trp. To this end, we recorded the average fluorescence lifetime, rotational correlation time and limiting anisotropy, dipolar relaxation time and limiting extent of relaxation, rate constant of acrylamide quenching, effect of H2O-D2O exchange, and time-resolved halfwidth of the spectrum in the absence and presence of POPC liposomes. Structure, localization, and hydration of the peptides were described by molecular dynamics simulations. The combination of the parameters provides a good description of the molecular environments of the Trp positions and the behavior of viscosin as a whole. Of particular value for characterizing the impact of viscosin on the membrane is the dipolar relaxation of Trp4 in V4W, which is deeply embedded in the hydrophobic core. The limiting relaxation level represents the membrane perturbation – unlike typical membrane probes – at the site of the perturbant. Fractions of Trp4 relax at different rates; the one not in contact with water upon excitation relaxes via recruitment of a water molecule on the 10 ns time scale. This rate is sensitive to the concerted membrane perturbation by more than one lipopeptide, which appears at high lipopeptide concentration and is assumed a prerequisite for the final formation of a membrane-permeabilizing defect. Trp7 relaxes primarily with respect to neighboring Ser residues. Trp5 flips between a membrane-inserted and surface-exposed orientation.
Contamination of aquatic environments has been steadily increasing due to human activities. The Pacific oyster Crassostrea gigas has been used as a key species in studies assessing the impacts of ...contaminants on human health and the aquatic biome. In this context, cytochrome P450 (CYPs) play a crucial role in xenobiotic metabolism. In vertebrates many of these CYPs are regulated by nuclear receptors (NRs) and little is known about the NRs role in C. gigas. Particularly, the CgNR5A represents a homologue of SF1 and LRH-1 found in vertebrates. Members of this group can regulate genes of CYPs involved in lipid/steroid metabolism, with their activity regulated by other NR, called as DAX-1, generating a NR complex on DNA response elements (REs). As C. gigas does not exhibit steroid biosynthesis pathways, CgNR5A may play other physiological roles. To clarify this issue, we conducted an in silico investigation of the interaction between CgNR5A and DNA to identify potential C. gigas CYP target genes. Using molecular docking and dynamics simulations of the CgNR5A on DNA molecules, we identified a monomeric interaction with extended REs. This RE was found in the promoter region of 30 CYP genes and also the NR CgDAX. When the upstream regulatory region was analyzed, CYP2C39, CYP3A11, CYP4C21, CYP7A1, CYP17A1, and CYP27C1 were mapped as the main genes regulated by CgNR5A. These identified CYPs belong to families known for their involvement in xenobiotic and lipid/steroid metabolism. Furthermore, we reconstructed a trimeric complex, previously proposed for vertebrates, with CgNR5A:CgDAX and subjected it to molecular dynamics simulations analysis. Heterotrimeric complex remained stable during the simulations, suggesting that CgDAX may modulate CgNR5A transcriptional activity. This study provides insights into the potential physiological processes involving these NRs in the regulation of CYPs associated with xenobiotic and steroid/lipid metabolism.
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•3D modeling and molecular dynamics simulations of the NR5A were conducted, predicting a monomeric DNA binding interaction.•CYP2C39, CYP3A11, CYP4C21, CYP7A1, CYP17A1, CYP27C1 and CgDAX genes, have been identified as promising targets of CgNR5A.•Molecular dynamics simulations of CgNR5A-CgDAX suggest a potential regulatory role of CgDAX in the activity of CgNR5A.
Two proinflammatory cytokines, IL17A and IL18, are observed to be elevated in the serum of gout patients and they play a crucial role in the development and worsening of inflammation, which has ...severe effects. In present study, we have combined molecular docking, molecular dynamics studies and MM-PBSA analysis to study the effectiveness of ethoxy phthalimide pyrazole derivatives (series 3a to 3e) as potential inhibitors against cytokines IL17A and IL18 as a druggable targets. The binding energy of the docked series ranges from −13.5 to −10.0 kcal/mol and extensively interacts with the amino acids in the active pocket of IL17A and IL18. Compound 3e had the lowest binding energy with IL17A at −12.6 kcal/mol compared to control allopurinol (3.32 kcal/mol). With IL18, compound 3a seems to have the lowest binding energy of −9.6 kcal/mol compared to control allopurinol (3.18 kcal/mol). In MD simulation studies, compound 3a forms a stable and energetically stabilized complex with the target protein. Depending on properties of the bound IL17A-3a and IL18-3a complexes was compared by means of MM-PBSA analysis. These derivatives can be used as a scaffold to develop promising IL17A and IL18 inhibitors to assess their potential for gouty arthritis and other related diseases.
Communicated by Ramaswamy H. Sarma
The aggregation of human γ-D crystallin is associated with the age-onset cataract formation. Here, we extensively investigated the self-association mechanism of human γ-D crystallin through molecular ...dynamics computer simulations. By mutating the protein surface we found that electrostatic interactions between charged amino acids play a crucial role in its self-association. We have confirmed the two-fold role of arginine molecules. If they are located as residues on the protein surface they can initiate protein contacts and contribute to their stickiness with noteworthy hydrophobic interactions through stacking of their methylene groups. But if they are added as free arginine in the protein solution they can also stabilize it, by associating with the protein surface and also with themselves to form effective inter-protein spacers that obstruct protein aggregation.
•Upon addition of 0.6 M free ARG, it self-assembles and interacts with the protein surface, which reduces protein aggregation.•Electrostatic interactions between charged residues on γ-D crystallin surface play the key role in its self-association.•Surface and free ARG can form non-negligible parallel and anti-parallel hydrophobic interactions through their -CH2 groups.•Covering the protein surface with LYS more enriched with -CH2 groups than ARG further enhances the protein self-assembly.
Chitosan (CS), the second most plentiful natural polysaccharide next to cellulose, has valuable characteristics including biocompatibility, nontoxicity and biodegradability. CS is broken down in the ...human body to innocuous products (amino sugars). Hydrogels are polymeric materials with three dimensional networks retaining a huge quantity of water within their structures which are of great interest in biomedical/environmental applications. Usually, injectable hydrogels have functional groups which are sensitive to pH, temperature or irradiation stimuli. Injectable scaffolds can be formed in situ through stimuli-responsive effect and they can overcome the drawback of traditional scaffolds which require surgery in order to be placed on the desired tissue. The antibacterial/antifungal activities of chitosan-based hydrogels and their applications in controlled drug delivery/release systems, tissue engineering, preparation of injectable hydrogels and water treatment (removal of heavy/toxic metals and dyes) will be described. Moreover, the molecular dynamics (MD) simulation were performed on the delivery of the anticancer chlorambucil (CB) drug using three silica filled polymeric nanocomposites based on chitosan (CS), polylactic acid (PLA) and polyethylene glycol (PEG) and it was illustrated that among three drug delivery systems (DDSs), the CS nanocomposite was the most efficient DDS due to the lowest drug diffusion was measured for the CS system that could lead to the most sustained/controlled drug delivery.
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•Antibacterial/antifungal activities of chitosan (CS)-based hydrogels were reviewed.•Application of CS-based hydrogels was studied in controlled drug delivery/release.•Application of CS-based hydrogels was investigated in tissue engineering.•Application of CS hydrogels was studied in water treatment (heavy ions/dyes removal).•MD simulations were performed on polymeric nanocomposite drug delivery systems.
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