ReaxFF molecular dynamics study on the shock-induced initiation mechanisms of ordered and disordered TNT/CL-20 coated models

The virial stress is the most commonly used definition of stress in discrete particle systems. This quantity includes two parts. The first part depends on the mass and velocity (or, in some versions, the fluctuation part of the velocity) of atomic particles, reflecting an assertion that mass transfer causes mechanical stress to be applied on stationary spatial surfaces external to an atomic‐particle system. The second part depends on interatomic forces and atomic positions, providing a continuum measure for the internal mechanical interactions between particles. Historic derivations of the virial stress include generalization from the virial theorem of Clausius (1870) for gas pressure and solution of the spatial equation of balance of momentum. The virial stress is stress‐like a measure for momentum change in space. This paper shows that, contrary to the generally accepted view, the virial stress is not a measure for mechanical force between material points and cannot be regarded as a measure for mechanical stress in any sense. The lack of physical significance is both at the individual atom level in a time‐resolved sense and at the system level in a statistical sense. It is demonstrated that the interatomic force term alone is a valid stress measure and can be identified with the Cauchy stress. The proof in this paper consists of two parts. First, for the simple conditions of rigid translation, uniform tension and tension with thermal oscillations, the virial stress yields clearly erroneous interpretations of stress. Second, the conceptual flaw in the generalization from the virial theorem for gas pressure to stress and the confusion over spatial and material equations of balance of momentum in theoretical derivations of the virial stress that led to its erroneous acceptance as the Cauchy stress are pointed out. Interpretation of the virial stress as a measure for mechanical force violates balance of momentum and is inconsistent with the basic definition of stress. The versions of the virial‐stress formula that involve total particle velocity and the thermal fluctuation part of the velocity are demonstrated to be measures of spatial momentum flow relative to, respectively, a fixed reference frame and a moving frame with a velocity equal to the part of particle velocity not included in the virial formula. To further illustrate the irrelevance of mass transfer to the evaluation of stress, an equivalent continuum (EC) for dynamically deforming atomistic particle systems is defined. The equivalence of the continuum to discrete atomic systems includes (i) preservation of linear and angular momenta, (ii) conservation of internal, external and inertial work rates, and (iii) conservation of mass. This equivalence allows fields of work‐ and momentum‐preserving Cauchy stress, surface traction, body force and deformation to be determined. The resulting stress field depends only on interatomic forces, providing an independent proof that as a measure for internal material interaction stress is independent of kinetic energy or mass transfer.

COVID-19 is caused by the SARS-CoV-2 virus. In this study, around 300 herbal compounds were screened virtually to find the best anti-COVID-19 structures. An extensive search in electronic databases was done. Around 300 herbal compounds, which were previously proven to be antiviral structures, were extracted from articles and considered our primary database. Then, molecular docking studies were performed to find the best inhibitors of the main SARS-COV-2 proteins, including spike protein (PDB 7BWJ), RNA-dependent RNA polymerase (PDB 6M71) and main protease (PDB 5R7Z). The molecular docking and dynamics studies revealed that fangchinoline as an alkaloid could bind to the main protease of the virus more potent than lopinavir (-42.26 vs. -30.9 kJ/mol). Fangchinoline can be orally active based on drug-like properties. According to the molecular dynamic study, the complex between the fangchinoline and SARS-CoV-2 main protease is stable. chebulagic acid is a benzopyrene tannin that could inhibit RNA-dependent RNA polymerase (RdRp) better than remdesivir (-43.9 vs. -28.8 kJ/mol). The molecular dynamic study showed that chebulagic acid-RdRp interaction is stable and strong. Furthermore, suramin could neutralize different variants of COVID-19 spike proteins (wild type, and alpha and beta variants). However, suramin is not orally active but it is a potential inhibitor for different coronavirus spike proteins. According to the promising in silico results of this study, fangchinoline, chebulagic acid and suramin could be introduced as potential lead compounds for COVID-19 treatment. We are hopeful to find a reliable remedy shortly through natural compounds.

BackgroundActivation of WNT signalling pathway was involved in a neuroprotective mechanism against amyloid beta toxicity (1). Inhibition of this pathway is associated with GSK‐3 beta activation, tau hyperphosphorylation, neuronal apoptosis (1), (2) and is implicated in Alzheimer’s disease (1). DKK‐1 competes with Wnt for the binding to LRP5/6 receptor (3) and disrupts the Wnt‐induced Fzd‐Wnt‐LRP6 complex (4) and thus antagonizes the neuro‐protective effect of WNT. In this study, we have targeted the DKK‐LRP interaction through virtual screening the first time to develop novel anti‐Alzheimer’s agent.MethodBased upon crystal structure information and protein validation using Ramachandran Plots, a crystal structure (PDB: 3S8V) was selected for further works. In this study, we have targeted the surface of LRP 5/6, which is interacting with DKK and grid was generated on LRP. The virtual screening of Asinex database library (N=19642) was done against this grid. Molecules were selected on the basis of good dock score and binding free energy calculation using MMGBSA in Schrodinger GLIDE (5)(6). The protein ligand complex structure stability were also evaluated by molecular dynamic simulation study (7). ADMET profile of the screened ligands were evaluated using Quick prop module of Schrodinger.ResultAfter running the virtual screening protocol (HTVS: SP: XP), 14 compounds were screened out, which showed significant binding top the DKK1 binding interface of LRP. These compounds were further evaluated on basis of docking score and MMGBSA. On the basis of After then on the basis of ADME profile selected 2 compound id ZINC000100138828 and ZINC000247940500 for further molecular dynamic simulation study which were shown the compound ZINC000100138828 had an avg. RMSD of ∼4.0Å, also the RMSF is 2.4 Å for overall protein side chain residue was reduced with reference to the apo form. It is displays rich interaction profile and strength with core binding residues (A: Pro833, B: Tyr706, B: Glu708, B: Arg751 and B: Ile681).ConclusionZINC000100138828 is a potent binder to the DKK1 binding surface on LRP5/6. It needs further in‐vitro and preclinical validation as a potential anti‐Alzheimer’s agent.

Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system that controls voluntary muscles; characterised by a slowly progressive weakness and stiffness of leg upper motor neuron syndrome. Many effective drugs act by modulating multiple targets, Drug repositioning/Drug repurposing can be used as an alternative methodology for drug discovery, and this ‘poly-pharmacology’ can be a therapeutic requirement for complex diseases. This study focuses on repurposing of FDA approved drugs against Transactive response DNA binding protein of 43 kDa (TDP43) protein of PLS disease by molecular docking and dynamic studies. The ligands were chosen from the FDA-approved chemical list and the target receptor was retrived from protein data bank (PDB ID: 7Q8V). The molecular docking study was carried out using the AutoDock Vina program and the results were visualised through Discovery studio tool. The ADMET features of top 10 drugs were predicted using pkCSM online software. Molecular dynamic study was carried out by Desmond. Several drugs showed extremely high binding free energies for chosen target of TDP43 Protein. The results have led to the discovery of Indinavir, Adapalene, Alclometasone, Amsacrine and other FDA-approved drugs as potential candidates for the treatment of PLS. Molecular dynamic studies were carried out for the best two complexes, complex was found to be stable during molecular dynamic simulation. This study led to the identify of Indinavir and Amsacrine as potential candidates for the treatment of PLS. Hence these drugs can be evaluated further in animal model to establish drug for treating PLS.

CYP450 aromatase catalyzes the terminal and rate-determining step in estrogen synthesis, the aromatization of androgens, and its inhibition is an efficient approach to treating estrogen-dependent breast cancer. Insight into the molecular basis of the interaction at the catalytic site between CYP450 aromatase inhibitors and the enzyme itself is required in order to design new and more active compounds. Hence, a combined molecular docking-molecular dynamics study was carried out to obtain the structure of the lowest energy association complexes of aromatase with some third-generation aromatase inhibitors (AIs) and with other novel synthesized letrozole-derived compounds which showed high in vitro activity. The results obtained clearly demonstrate the role of the pharmacophore groups present in the azaheterocyclic inhibitors (NSAIs)-namely the triazolic ring and highly functionalized aromatic moieties carrying H-bond donor or acceptor groups. In particular, it was pointed out that all of them can contribute to inhibition activity by interacting with residues of the catalytic cleft, but the amino acids involved are different for each compound, even if they belong to the same class. Furthermore, the azaheterocyclic group strongly coordinates with the Fe(II) of heme cysteinate in the most active NSAI complexes, while it prefers to adopt another orientation in less active ones.

Background: The outbreak of the global pandemic COVID-19 has infected and killed more than millions of people in a short period of time. Given the condition, there is an urgent need for developing anti-viral therapy for eradicating the coronavirus. Plant metabolites remain to be valuable resources in treating various ailments, including viral diseases. Since Clausena anisata (CA) has been reported for its antiviral activity, exploration of anti coronavirus activity will lead to the development of anti coronavirus drug molecules. Protease enzymes play a crucial role in the process of converting the core proteins into structural and functional proteins,which is essential for the survival of coronavirus life cycle. Hence, proteases, such as main protease and papain like protease, were selected therapeutic targets to explore the anti-COVID activity of CA. Objectives: The present study aims to carry out insilico molecular docking, ADME-Tox prediction and molecular dynamic studies to unfold the possible protease inhibitory activities of phyto principles of CA against main protease (Mpro) and papain like protease (PLpro) of SARS-CoV-1& 2. Methods: All the insilico studies were carried out using Schrödinger software. Molecular docking studies were carried out targeting main protease (PDB ID: 2GTB, 6LU7) and papain-like protease (PDB ID: 4OW0, 7CMD), which were retrieved from the Protein Data Bank (PDB). Studies were also conducted on the absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. Molecular dynamic simulation study was carried out to observe the behaviour of the Ligandtarget complex and to calculate the stability over time on the top-scored phytoprinciples of CA. Results and Discussion: Out of 139 phyto principles selected for the study, some phytoprinciples, such as Heptaphylline, Clausenamide, indicolactone, and xanthotaxol showed better docking scores. The phytoprinciples of CA interacted with Mpro and PLpro of both SARS-CoV-1& 2. These phyto compounds were found to have molecular interaction with the essential amino acid residues, such as TYR 268, ASP 164, GLN 269, Trp106, Asn109, Lys232, Pro247, His272, Asp286 and Thr301 of PLpro and HIS 41, Glu 166 and Cys 145 of Mpro. Molecular dynamics study demonstrated the stability of the phytochemicals-target complexes. ADME-Tox prediction results showed the drug likeness and non-toxic nature of the phytoprinciples selected for the study. Conclusion: The anti-coronavirus activity of CA was explored by in silico studies. The molecular docking studies against proteases of SARS-CoV-1& 2 indicate that CA has the anti-coronavirus activity through interacting with the main protease and papain protease. The combined PLpro and Mpro inhibitory activity of CA will have additional benefit in restricting the survival coronaviruses. This study will be a base for exploring the anti-coronavirus activity of CA in multiple directions to obtain a novel anti COVID lead molecules.

A computational journey in anticancer drug discovery: Exploring AKT1 inhibition by novel oxadiazoles using molecular docking, ADMET, density functional theory and molecular dynamic simulation.

While examining PFPE (perfluoropolyether)-based disk lubricants, extra lability was suspected for a hydrogen-bonded pair of hydroxy end-groups in the presence of a nucleophile (electron donor). Plausible reaction sequences upon electron capture of hydrogen-bonded methanol dimer, hydrogen-bonded ethanol dimer, and 1,2-propanediol were first examined by a molecular dynamics method based on the potential given by a semiempirical SCF molecular orbital calculation, and subsequently by matrix isolation ESR spectroscopy. In the latter experimental study, alcohol dimer anions were generated by co-trapping Na atoms and alcohol molecules in argon matrices and inducing electron transfer by photo-irradiation. In the cases of methanol and ethanol dimers, the molecular dynamics study predicted that on capture of an electron, the hydroxy hydrogen of the acceptor side would cleave as an atom, and then abstract a hydrogen atom from the nearest carbon of the proton donating alcohol. For 1,2-propanediol anion, the molecular dynamics study predicted C1–C2 bond scission followed by abstraction of the C2 hydroxy hydrogen by the C1 radical fragment. The matrix isolation ESR study revealed generation of radicals upon photo-irradiation when the alcohol concentration was sufficiently high to warrant the presence of dimers. The spectral patterns thus observed were totally consistent with the radical products predicted by the molecular dynamics calculations.

BackgroundThe new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified at the end of 2019. Despite growing understanding of SARS-CoV-2 in virology as well as many molecular studies, except remdesivir, no specific anti-SARS-CoV-2 drug has been officially approved.MethodsIn the present study molecular docking technique was applied to test binding affinity of ciprofloxacin and levofloxacin—two commercially available fluoroquinolones, to SARS-CoV-2 S-, E- and TMPRSS2 proteins, RNA-dependent RNA polymerase and papain-like protease (PLPRO). Chloroquine and dexamethasone were used as reference positive controls.ResultsWhen analyzing the molecular docking data it was noticed that ciprofloxacin and levofloxacin possess lower binding energy with S protein as compared to the references. In the case of TMPRSS2 protein and PLPRO protease the best docked ligand was levofloxacin and in the case of E proteins and RNA-dependent RNA polymerase the best docked ligands were levofloxacin and dexamethasone. Moreover, a molecular dynamics study also reveals that ciprofloxacin and levofloxacin form a stable complex with E- and TMPRSS2 proteins, RNA polymerase and papain-like protease (PLPRO).ConclusionsThe revealed data indicate that ciprofloxacin and levofloxacin could interact and potentially inhibit crucial SARS-CoV-2 proteins.

Background: Overexpressed CDK1 and CDK2 are targeted as potential sites for cancer treatment. Annona muricata fruit has been reported to have more than 100 acetogenins showing cytotoxic activities against cancer cell lines. Hence the study aims to demonstrate the cytotoxicity of ethyl acetate fruit extract, its role in cell cycle progression, and apoptosis using the MDMBA-231 breast cancer cell line. Docking, dynamics, and ADME studies were also demonstrated to generate lead molecules of AM fruit responsible for cancer treatment. Method: Cell viability was quantified by the MTT assay. Cell cycle arrest and apoptotic cells were determined by flow cytometry and PI annexin V-FITC staining by flow cytometry, respectively. Molecular docking, molecular dynamics, and ADME properties of 11 acetogenins were studied using the schrödinger maestro suite 2018-1. Results: The MTT assay revealed IC50 232.9μg/ml with a high degree of cytotoxicity. The extract effectively caused cell cycle arrest at the G2M and S phases; early and late apoptosis was induced at 160 μg/ml and 320 μg/ml. Docking scores of muricin L, J, and annomuricin A complexed with CDK2 and muricin J, K, and L with CDK1 binding energy ranging is mentioned as a molecular dynamic study envisaged muricin j against CDK2 stable hydrogen and hydrophobic interactions with critical residues like ASP-86, GLN-131, HIS-84, LYS-89, PHE80, PHE82, and PHE83 throughout 200 ns (hinge region). ADMET profiling also confirmed that all 11 ligands passed the rule of 5 and 3. The in vitro and in silico studies revealed that these acetogenins could be CDK1 and CDK2 inhibitors for cancer treatment. Conclusion: The in vitro studies presume that the ethyl acetate fruit extract of AM is an excellent cytotoxic agent. In silico studies demonstrated that muricin j could lead molecules to target kinase proteins responsible for cell proliferation. ADME study enlightened us to take 11 acetogenins for the drug discovery process in managing cancer treatment.

Classical molecular dynamics (MD) study was performed in order to explain a different wettability of silanized silica-glass surfaces prepared by using two different precursors – dichlorodimethylsilane (DCDMS) and dimethyldiethoxysilane (DMDES), respectively. Whereas the modified surface prepared by DCDMS becomes hydrophobic (contact angle (CA) of water >90°), DMDES-modified surface stays partially hydrophilic (CA ∼39°). In order to explain the observed discrepancy, several models of surfaces of trydimite with different coating by (CH3)2–Si= units were constructed and treated by water nanodroplets in the MD simulations. The models of surfaces differ by a different degree of surface coverage and/or oligomerized (CH3)2–Si= units in a lateral dimension. The simulations showed that incomplete coverage leads to a decrease of the computed CA, whereas upon lateral oligomerization the CA increases. This variation of the CA is directly related to the accessible amount of the hydroxyl groups on the surfaces and can be a possible explanation of the difference in wettability between DCDMS- and DMDES-treated glass surfaces.

COPD is a multifactorial lung disease causing breathing difficulties in individuals and is becoming a major health concern worldwide. The unclear pathogenic mechanism and high mortality rate urge the development of drugs against this disease. In this study, around six COPD biomarkers identified from the preceding research through integrated gene expression analysis were taken as COPD target proteins. A total of 3307 phytocompounds were included in the COPD phytocompound library from 59 therapeutic plant sources. Furthermore, a crucial three-step virtual screening process (Absorption, Distribution, Metabolism, and Excretion, respiratory nontoxicity, less harmful and nontoxic compound category) was implemented to filter the potential drug-like phytocompounds. As a result, 160 phytocompounds were filtered with desired Absorption, Distribution, Metabolism, Excretion and Toxicity properties. The filtered 160 phytocompounds were docked against six COPD target proteins and the best-docked complexes were identified through visual inspection based on six unique parameters in SeeSAR. Furthermore, the best docked complexes were subjected to molecular dynamics simulation studies to assess the stability and conformational changes of the complexes. The presence of few amino acid residues within the crucial active, allosteric and catalytic sites of the six target proteins were revealed from the binding interaction types and major residual fluctuations from molecular docking and dynamic simulation studies respectively. This is indicative of the potential inhibitory activity of phytocompounds against the COPD biomarkers. Here we report the identified phytocompounds as a promising lead molecule for the six COPD biomarkers through in silico analysis opening new avenues in COPD pathogenesis and treatments. Communicated by Ramaswamy H. Sarma

Molecular dynamics (MD) study on glycolic acid in the physiological salt solution has been performed, which is a model of a biofuel cell. The structure and charge distribution of glycolic acid in aqueous solution used in MD is beforehand optimized by Gaussian09 utilizing the density functional theory. MD is performed in the NTV constant condition, i.e. the number of particles, temperature, and volume of MD cell are definite. The structure difference of the glycolic acid and oxalic acid is detected by the water distribution around the molecules using the pair distribution functions, gij(r), and the frequency dependent diffusion coefficients, Di(ν). The anomalous dielectric constant of the solution, i.e. about 12 times larger than that of water, has been obtained, which may be attributed to the ion pair formation in the solution.

Objective D-Limonene (D-LMN) is a potential anti-oral cancer agent. The incorporation of D-LMN into a nanoemulsion enhances its potential efficacy against oral cancer cells by improving its aqueous compatibility. This study evaluated the impact of surfactant type and concentration on their properties through experimental and molecular dynamics studies. Methods D-LMN nanoemulsions were produced using different polyoxyethylene nonionic surfactants. The nanoemulsions were compared on droplet size, size distribution, zeta potential, droplet morphology, stability, interaction among molecules, anticancer activity, and cell death mechanism. Molecular dynamics simulations were also conducted to elucidate the dynamics of the components. Results Cremophor RH40 and Tween 60 yielded a nanoemulsion with a small droplet size (<100 nm). Cremophor RH40 also produced the nanoemulsion with the narrowest size distribution. Two-dimensional nuclear Overhauser effect spectroscopy–nuclear magnetic resonance and molecular dynamic simulation studies revealed that Cremophor RH40 effectively produced nanoemulsions with small droplets and high stability. The nanoemulsions formulated with Tween 60 exhibited more potent inhibitory effects against oral cancer cells than those with Cremophor RH40. However, surfactant type did not influence the mechanism underlying the apoptotic. Conclusions This study demonstrated that surfactants with an intermediate hydrophilic–lipophilic balance of approximately 15, particularly those with large polar heads and multiple hydrocarbon chains, were suitable for the production of anti-oral cancer D-LMN nanoemulsions by phase-inversion temperature technique.

Effect of sodium alkyl sulfate chain length on foam stability: A molecular dynamics study