Combining SARS-CoV-2 Proofreading Exonuclease and RNA-Dependent RNA Polymerase Inhibitors as a Strategy to Combat COVID-19: A High-Throughput in silico Screening

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worldwide. Currently, many clinical trials in search of effective COVID-19 drugs are underway. Viral RNA-dependent RNA polymerase (RdRp) remains the target of choice for prophylactic or curative treatment of COVID-19. Nucleoside analogs are the most promising RdRp inhibitors and have shown effectiveness in vitro, as well as in clinical settings. One limitation of such RdRp inhibitors is the removal of incorporated nucleoside analogs by SARS-CoV-2 exonuclease (ExoN). Thus, ExoN proofreading activity accomplishes resistance to many of the RdRp inhibitors. We hypothesize that in the absence of highly efficient antivirals to treat COVID-19, combinatorial drug therapy with RdRp and ExoN inhibitors will be a promising strategy to combat the disease. To repurpose drugs for COVID-19 treatment, 10,397 conformers of 2,240 approved drugs were screened against the ExoN domain of nsp14 using AutoDock VINA. The molecular docking approach and detailed study of interactions helped us to identify dexamethasone metasulfobenzoate, conivaptan, hesperidin, and glycyrrhizic acid as potential inhibitors of ExoN activity. The results were further confirmed using molecular dynamics (MD) simulations and molecular mechanics combined with generalized Born model and solvent accessibility method (MM-GBSA) calculations. Furthermore, the binding free energy of conivaptan and hesperidin, estimated using MM-GBSA, was −85.86 ± 0.68 and 119.07 ± 0.69 kcal/mol, respectively. Based on docking, MD simulations and known antiviral activities, and conivaptan and hesperidin were identified as potential SARS-CoV-2 ExoN inhibitors. We recommend further investigation of this combinational therapy using RdRp inhibitors with a repurposed ExoN inhibitor as a potential COVID-19 treatment.

Dynamics of a vector-borne model with direct transmission and age of infection.

In this paper we the study of dynamics of time since infection structured vector born model with the direct transmission. We use standard incidence term to model the new infections. We analyze the corresponding system of partial di erential equation and obtain an explicit formula for the basic reproduction number R0. The diseases-free equilibrium is locally and globally asymptotically stable whenever the basic reproduction number is less than one, R0 < 1. Endemic equilibrium exists and is locally asymptotically stable when R0 > 1. The disease will persist at the endemic equilibrium whenever the basic reproduction number is greater than one.

MMGB/SA Consensus Estimate of the Binding Free Energy Between the Novel Coronavirus Spike Protein to the Human ACE2 Receptor

The ability to estimate protein-protein binding free energy in a computationally efficient via a physics-based approach is beneficial to research focused on the mechanism of viruses binding to their target proteins. Implicit solvation methodology may be particularly useful in the early stages of such research, as it can offer valuable insights into the binding process, quickly. Here we evaluate the potential of the related molecular mechanics generalized Born surface area (MMGB/SA) approach to estimate the binding free energy ΔGbind between the SARS-CoV-2 spike receptor-binding domain and the human ACE2 receptor. The calculations are based on a recent flavor of the generalized Born model, GBNSR6. Two estimates of ΔGbind are performed: one based on standard bondi radii, and the other based on a newly developed set of atomic radii (OPT1), optimized specifically for protein-ligand binding. We take the average of the resulting two ΔGbind values as the consensus estimate. For the well-studied Ras-Raf protein-protein complex, which has similar binding free energy to that of the SARS-CoV-2/ACE2 complex, the consensus ΔGbind = −11.8 ± 1 kcal/mol, vs. experimental −9.7 ± 0.2 kcal/mol.The consensus estimates for the SARS-CoV-2/ACE2 complex is ΔGbind = −9.4 ± 1.5 kcal/mol, which is in near quantitative agreement with experiment (−10.6 kcal/mol). The availability of a conceptually simple MMGB/SA-based protocol for analysis of the SARS-CoV-2 /ACE2 binding may be beneficial in light of the need to move forward fast.

The Born Model Can Accurately Describe Electrostatic Ion Solvation.

<p>Accurate models of the free energies of ions in solution are crucial for understanding and modelling the huge number of important applications where electrolyte solutions play a crucial role such as electrochemical energy storage. The Born model, developed to describe ion solvation free energies, is widely considered to be critically flawed as it predicts a linear response of water to ionic charge, which fails to match water's supposed intrinsic preference to solvate anions over cations. Here, we demonstrate that this asymmetric response observed in simulation is the result of an arbitrary choice that the oxygen atom should be the centre of a water molecule. We show that an alternative and reasonable choice, which places the centre 0.5 Å towards the hydrogen atoms, results in a linear and charge symmetric response of water to ionic charge for a classical water model consistent with the Born model. This asymmetry should therefore be regarded as a property of the short range repulsive interaction not an intrinsic electrostatic property of water. We also show that this new water centre results in a more reasonable neutral cavity potential. </p><p></p>

The Born Model Can Accurately Describe Electrostatic Ion Solvation.

<p>Accurate models of the free energies of ions in solution are crucial for understanding and modelling the huge number of important applications where electrolyte solutions play a crucial role such as electrochemical energy storage. The Born model, developed to describe ion solvation free energies, is widely considered to be critically flawed as it predicts a linear response of water to ionic charge, which fails to match water's supposed intrinsic preference to solvate anions over cations. Here, we demonstrate that this asymmetric response observed in simulation is the result of an arbitrary choice that the oxygen atom should be the centre of a water molecule. We show that an alternative and reasonable choice, which places the centre 0.5 Å towards the hydrogen atoms, results in a linear and charge symmetric response of water to ionic charge for a classical water model consistent with the Born model. This asymmetry should therefore be regarded as a property of the short range repulsive interaction not an intrinsic electrostatic property of water. We also show that this new water centre results in a more reasonable neutral cavity potential. </p><p></p>

A priori analysis of a higher-order nonlinear elasticity model for an atomistic chain with periodic boundary condition

Nonlinear elastic models are widely used to describe the elastic response of crystalline solids, for example, the well-known Cauchy–Born model. While the Cauchy–Born model only depends on the strain, effects of higher-order strain gradients are significant and higher-order continuum models are preferred in various applications such as defect dynamics and modeling of carbon nanotubes. In this paper we rigorously derive a higher-order nonlinear elasticity model for crystals from its atomistic description in one dimension. We show that, compared to the second-order accuracy of the Cauchy–Born model, the higher-order continuum model in this paper is of fourth-order accuracy with respect to the interatomic spacing in the thermal dynamic limit. In addition we discuss the key issues for the derivation of higher-order continuum models in more general cases. The theoretical convergence results are demonstrated by numerical experiments.

The Born model can accurately describe electrostatic ion solvation

The solvation free energies of ions in water are consistent with the Born linear response model if the centre on which the ion–water repulsion force acts is moved from the oxygen atom towards the hydrogens.

Influence of plasticizer nature on the analytical characteristics of ion-selective electrodes based on higher quaternary ammonium salts reversible to doubly charged inorganic anions

It has been established that membranes of carbonate and hydrogen phosphate selective electrodes based on higher quaternary ammonium salts are preferable to be plasticized with o-nitrophenyldecyl ether, membranes of sulfate, selenate, selenite-selective electrodes with 1-bromonaphthalene, sulfite, molybdate, tungstate-selective electrodes with dibutylphthalate. The use of an optimum plasticizer allows, in general, reducing both the lower detection limit of electrodes and the values of selectivity coefficients by about 1 order (depending on the interfering ion). A qualitative explanation is given to the results obtained from the Fouoss theory and the Born model.

Запрещенное резонансное комбинационное рассеяние света в сверхрешетках GaAs/AlAs: эксперимент и расчеты

The Raman spectra of GaAs/AlAs(100) superlattices are calculated and studied experimentally for various wave-vector directions. The experiments are performed when applying a confocal optical microscope combined with a micro-Raman spectrometer for various scattering geometries both for phonons with a wave vector directed along the normal to a superlattice and in the in-plane geometry. The frequencies and eigenvectors of phonons are calculated in the extended Born model approximation taking into account Coulomb interaction in the rigid-ion approximation. The Raman spectra are calculated in the scope of the deformation- potential mechanism; herewith, it turns out that additional peaks, which are not described in the scope of this approach, appear in the experimental spectra. It seems likely that these peaks appear due to the manifestation of Raman scattering forbidden by selection rules under resonance conditions. An attempt is made to explain the appearance of these peaks in the experimental spectra within the scope of inelastic phonon scattering at bound charges (phonons with a large dipole moment).