Integrated docking and enhanced sampling-based selection of repurposing drugs for SARS-CoV-2 by targeting host dependent factors.

Since the onset of global pandemic, the most focused research currently in progress is the development of potential drug candidates and clinical trials of existing FDA approved drugs for other relevant diseases, in order to repurpose them for the COVID-19. At the same time, several high throughput screenings of drugs have been reported to inhibit the viral components during the early course of infection but with little proven efficacies. Here, we investigate the drug repurposing strategies to counteract the coronavirus infection which involves several potential targetable host proteins involved in viral replication and disease progression. We report the high throughput analysis of literature-derived repurposing drug candidates that can be used to target the genetic regulators known to interact with viral proteins based on experimental and interactome studies. In this work we have performed integrated molecular docking followed by molecular dynamics (MD) simulations and free energy calculations through an expedite in silico process where the number of screened candidates reduces sequentially at every step based on physicochemical interactions. We elucidate that in addition to the pre-clinical and FDA approved drugs that targets specific regulatory proteins, a range of chemical compounds (Nafamostat, Chloramphenicol, Ponatinib) binds to the other gene transcription and translation regulatory proteins with higher affinity and may harbour potential for therapeutic uses. There is a rapid growing interest in the development of combination therapy for COVID-19 to target multiple enzymes/pathways. Our in silico approach would be useful in generating leads for experimental screening for rapid drug repurposing against SARS-CoV-2 interacting host proteins.Communicated by Ramaswamy H. Sarma.

Metadynamics-based enhanced sampling protocol for virtual screening: case study for 3CLpro protein for SARS-CoV-2.

In recent times, computational methods played an important role in the down selection of chemical compounds, which could be a potential drug candidate with a high affinity to target proteins. However, the screening methodologies, including docking, often fails to identify the most effective compound, which could be a ligand for the target protein. To solve that, here we have integrated meta-dynamics, an enhanced sampling molecular simulation method, with all-atom molecular dynamics to determine a specific compound that could target the main protease of novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). This combined computational approach uses the enhanced sampling to explore the free energy surface associated with the protein's binding site (including the ligand) in an explicit solvent. We have implemented this method to find new chemical entities that exhibit high specificity of binding to the 3-chymotrypsin-like cysteine protease (3CLpro) present in the SARS-CoV-2 and segregated to the most strongly bound ligands based on free energy and scoring functions (defined and implemented) from a set of 17 ligands which were prescreened for synthesizability and druggability. Additionally, we have compared these 17 ligands' affinities against controls, N3 and 13b α-ketoamide inhibitors, for which experimental crystal structures are available. Based on our results and analysis from the combined molecular simulation approach, we could identify the best compound which could be further taken as a potential candidate for experimental validation.Communicated by Ramaswamy H. Sarma.

Magnetite-Coated Boron Nitride Nanosheets for the Removal of Arsenic(V) from Water.

It is widely known that the existence of arsenic (As) in water negatively affects humans and the environment. We report the synthesis, characterization, and application of boron nitride nanosheets (BNNSs) and Fe3O4-functionalized BNNS (BNNS-Fe3O4) nanocomposite for removal of As(V) ions from aqueous systems. The morphology, surface properties, and compositions of synthesized nanomaterials were examined using scanning electron microscopy, transmission electron microscopy, X-ray powder diffraction, surface area analysis, zero-point charge, and magnetic moment determination. The BNNS-Fe3O4 nanocomposites have a specific surface area of 119 m2 g-1 and a high saturation magnetization of 49.19 emu g-1. Due to this strong magnetic property at room temperature, BNNS-Fe3O4 can be easily separated in solution by applying an external magnetic field. From the activation energies, it was found that the adsorption of As(V) ions on BNNSs and BNNS-Fe3O4 was due to physical and chemical adsorption, respectively. The maximum adsorption capacity of BNNS-Fe3O4 nanocomposite for As(V) ions has been found to be 26.3 mg g-1, which is 5 times higher than that of unmodified BNNSs (5.3 mg g-1). This closely matches density functional theory simulations, where it is found that binding energies between BNNS-Fe3O4 nanocomposite and As(OH)5 are 5 times higher than those between BNNSs and As(OH)5, implying 5 times higher adsorption capacity of BNNS-Fe3O4 nanocomposite than unmodified BNNSs. More importantly, it was observed that the synthesized BNNS-Fe3O4 nanocomposite could reduce As(V) ion concentration from 856 ppb in a solution to below 10 ppb (>98.83% removal), which is the permissible limit according to World Health Organization recommendations. Finally, the synthesized adsorbent showed both separation and regeneration properties. These findings demonstrate the potential of BNNS-Fe3O4 nanocomposite for commercial application in separation of As(V) ions from potable and waste water streams.

Extraction of Gd3+ and UO22+ Ions Using Polystyrene Grafted Dibenzo Crown Ether (DB18C6) with Octanol and Nitrobenzene: A Molecular Dynamics Study.

Atomistic molecular dynamics (MD) simulations are performed in order to derive thermodynamic properties important to understand the extraction of gadolinium (Gd3+) and uranium dioxide (UO2) with dibenzo crown ether (DBCE) in nitrobenzene (NB) and octanol (OCT) solvents. The effect of polystyrene graft length, on DBCE, on the binding behavior of Gd3+ and UO22+ is investigated for the first time. Our simulation results demonstrate that the binding of Gd3+ and UO22+ onto the oxygens of crown ethers is favorable for polystyrene grafted crown ether in the organic solvents OCT and NB. The metal ion binding free energy (ΔGBinding) in different solvent environments is calculated using the thermodynamic integration (TI) method. ΔGBinding becomes more favorable in both solvents, NB and OCT, with an increase in the polystyrene monomer length. The metal ion transferability from an aqueous phase to an organic phase is estimated by calculating transfer free-energy calculations (ΔGTransfer). ΔGTransfer is significantly favorable for both Gd3+ and UO22+ for the transfer from the aqueous phase to the organic phase (i.e., NB and OCT) via ion-complexation to DBCE with an increase in polystyrene length. The partition coefficient (log P) values for Gd3+ and UO22+ show a 5-fold increase in separation capacity with polystyrene grafted DBCE. We corroborate the observed behavior by further analyzing the structural and dynamical properties of the ions in different phases.

An interaction potential to study the thermal structure evolution of a thermoelectric material: ß-Cu2 Se.

An interaction potential model has been developed, for the first time, for ß-Cu2 Se using the ab initio derived data. The structure and elastic constants of ß-Cu2 Se using the derived force-field are within a few percent of DFT derived structure and elastic constants and reported experimental structure. The derived force-field also shows remarkable ability to reproduce temperature dependent behavior of the specific heat and thermal expansion coefficient. The thermal structure evolution of the ß-Cu2 Se is studied by performing the molecular dynamic simulations using the derived force-field. The simulation results demonstrate that the Cu ions moves around the equilibrium lattice position within the temperature range of 500-800 K. However, at a temperature > 800 K, the Cu ions starts diffusing within the material, while the Se ions remains in their lattice position. The evaluated thermodynamic properties such as free energy and excess entropy, show that the increased Cu-Se interaction with the temperature makes the system more thermodynamically stable. © 2017 Wiley Periodicals, Inc.

Dewetting dynamics of a gold film on graphene: implications for nanoparticle formation.

The dynamics of dewetting of gold films on graphene surfaces is investigated using molecular dynamics simulation. The effect of temperature (973-1533 K), film diameter (30-40 nm) and film thickness (0.5-3 nm) on the dewetting mechanism, leading to the formation of nanoparticles, is reported. The dewetting behavior for films ≤5 Å is in contrast to the behavior seen for thicker films. The retraction velocity, in the order of ∼300 m s(-1) for a 1 nm film, decreases with an increase in film thickness, whereas it increases with temperature. However at no point do nanoparticles detach from the surface within the temperature range considered in this work. We further investigated the self-assembly behavior of nanoparticles on graphene at different temperatures (673-1073 K). The process of self-assembly of gold nanoparticles is favorable at lower temperatures than at higher temperatures, based on the free-energy landscape analysis. Furthermore, the shape of an assembled structure is found to change from spherical to hexagonal, with a marked propensity towards an icosahedral structure based on the bond-orientational order parameters.

Removal of Heavy Metal Ions Using a Functionalized Single-Walled Carbon Nanotube: A Molecular Dynamics Study.

The adsorption behaviors of heavy metal ions Cd(2+), Cu(2+), Pb(2+), and Hg(2+), in aqueous media using functionalized single-walled carbon nanotube (SWCNT) with functional groups -COO(-), -OH, and -CONH2 are studied using molecular dynamics (MD) simulations. The results show that adsorption capacity is improved significantly using surface modification of SWCNT with carboxyl, hydroxyl, and amide functional groups. In addition, the adsorption capacity is found to increase with increasing metal-ion concentration. It is observed that the CNT-COO(-) surface effectively adsorbs over 150-230% more metal ions than the bare CNT surface. On the contrary, -OH and -CONH2 are relatively weak functional groups where excess metal-ion adsorption compared to the bare CNT is in the range 10-47%. The structural properties, self-diffusion coefficients, and adsorption isotherms of the metal ions are computed and analyzed in detail. Moreover, the potential of mean force (PMF) is computed to understand the free energy of metal ions, in the presence of functional groups, which is remarkly higher in absolute terms, leading to significant affinity for adsorption compared to the case for the bare CNT. In general, the following order of adsorption of the metal ions on functionalized CNT is observed: Pb(2+) > Cu(2+) > Cd(2+) > Hg(2+).

Interaction potential models for bulk ZnS, ZnS nanoparticle, and ZnS nanoparticle-PMMA from first-principles.

An ab initio derived transferable polarizable force-field has been developed for Zinc sulphide (ZnS) nanoparticle (NP) and ZnS NP-PMMA nanocomposite. The structure and elastic constants of bulk ZnS using the new force-field are within a few percent of experimental observables. The new force-field show remarkable ability to reproduce structures and nucleation energies of nanoclusters (Zn1S1-Zn12S12) as validated with that of the density functional theory calculations. A qualitative agreement of the radial distribution functions of Zn-O, in a ZnS nanocluster-PMMA system, obtained using molecular mechanics molecular dynamics (MD) and ab initio MD (AIMD) simulations indicates that the ZnS-PMMA interaction through Zn-O bonding is explained satisfactorily by our force-field.