Mechanistic insights of key host proteins and potential repurposed inhibitors regulating SARS-CoV-2 pathway.

The emergence of pandemic situations originated from severe acute respiratory syndrome (SARS)-CoV-2 and its new variants created worldwide medical emergencies. Due to the non-availability of efficient drugs and vaccines at these emergency hours, repurposing existing drugs can effectively treat patients critically infected by SARS-CoV-2. Finding a suitable repurposing drug with inhibitory efficacy to a host-protein is challenging. A detailed mechanistic understanding of the kinetics, (dis)association pathways, key protein residues facilitating the entry-exit of the drugs with targets are fundamental in selecting these repurposed drugs. Keeping this target as the goal of the paper, the potential repurposing drugs, Nafamostat, Camostat, Silmitasertib, Valproic acid, and Zotatifin with host-proteins HDAC2, CSK22, eIF4E2 are studied to elucidate energetics, kinetics, and dissociation pathways. From an ensemble of independent simulations, we observed the presence of single or multiple dissociation pathways with varying host-proteins-drug systems and quantitatively estimated the probability of unbinding through these specific pathways. We also explored the crucial gateway residues facilitating these dissociation mechanisms. Interestingly, the residues we obtained for HDAC2 and CSK22 are also involved in the catalytic activity. Our results demonstrate how these potential drugs interact with the host machinery and the specific target residues, showing involvement in the mechanism. Most of these drugs are in the preclinical phase, and some are already being used to treat severe COVID-19 patients. Hence, the mechanistic insight presented in this study is envisaged to support further findings of clinical studies and eventually develop efficient inhibitors to treat SARS-CoV-2.

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.

Recent Advances in the Carrier Mobility of Two-Dimensional Materials: A Theoretical Perspective.

Since the breakthrough of graphene, 2D materials have engrossed tremendous research attention due to their extraordinary properties and potential applications in electronic and optoelectronic devices. The high carrier mobility in the semiconducting material is critical to guarantee a high switching speed and low power dissipation in the corresponding device. Here, we review significant recent advances and important new developments in the carrier mobility of 2D materials based on theoretical investigations. We focus on some of the most widely studied 2D materials, their development, and future applications. Based on the current progress in this field, we conclude the review by providing challenges and an outlook in this field.

Validation of Salivary Markers, IL-1ß, IL-8 and Lgals3bp for Detection of Oral Squamous Cell Carcinoma in an Indian Population.

Early detection and easier follow-up of oral squamous cell carcinoma (OSCC) would significantly improve the morbidity and mortality associated with it. With newer technologies, it has become possible to validate cancer biomarkers in saliva with high sensitivity and specificity. There is however a need to further validate these biomarkers in cohorts of different ethnic groups. Our objective was to validate previously evaluated salivary biomarkers in Indian population. The study enrolled 117 patients. These were grouped into subcatergories of 31 early (TNMstage I-II) and 27 late-stage OSCC (TNM stage III-IV), 30 PMOD and 29 post-treatment patients. There were 42 control subjects. We evaluated 3 protein markers, IL-1ß, IL-8 and LGALS3BP using ELISA, from unstimulated saliva samples. Statistical analysis was done to calculate p-value, ROC, AUC, sensitivity, and specificity. Protein markers IL-1ß and IL-8 were significantly elevated (p < 0.05) in OSCC patients. Though the markers could not discriminate PMOD and post-treatment subjects from controls, they proved to be significantly discriminatory between OSCC and controls. Both these markers were especially strong discriminators of late stage OSCC (stage III-IV). IL-1ß had the most statistically significant discriminative power (AUC = 0.9017) in late-stage OSCC followed by IL-8 (AUC = 0.7619). Although LGALS3BP was not found to be significantly elevated in late stage OSCC patients, but it was a significant discriminator of early stage OSCC (stage I-II) with p-value = 0.0008 and AUC = 0.7296. These salivary biomarkers have been discovered and validated in other ethnic groups earlier. Hence, the fact that these markers were discriminatory in Indian population too, strengthens the possibility of using these salivary biomarkers as screening tools in different ethnic cohorts. Such trials would potentiate use of a non-invasive tool, like saliva for diagnosis and follow-up of oral cancer.

Boron-Carbon-Nitride Sheet as a Novel Surface for Biological Applications: Insights from Density Functional Theory.

Understanding the interaction between nanoscale materials and nucleobases is essential for their use in nanobiotechnology and nanomedicine. Our ab initio calculations indicate that the interaction of nucleobases [adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U)] with boron-carbon-nitride (BCN) is mainly governed by van der Waals interactions. The adsorption energies, ranging from -0.560 to -0.879 eV, decrease in the order of G > A > T > C > U, which can be attributed to π-π interactions and different side groups of the nucleobases. We found that anions (N and O atoms) of nucleobases prefer to stay on top of cation (B) of the substrate. The results also showed that BCN exhibits superior binding strength than graphene and boron-nitride-based materials. We also found that upon adsorption, the fundamental properties of BCN and nucleobases remains unaltered, which suggests that BCN is a promising template for self-assembly of nucleobases.

Formation patterns of water clusters in CMK-3 and CMK-5 mesoporous carbons: a computational recognition study.

Grand canonical Monte Carlo simulations are performed to study the adsorption of water in realistic CMK-3 and CMK-5 models at 300 K. The adsorption isotherms are characterized by negligible uptake at lower chemical potentials and complete pore filling once the threshold chemical potential is increased. Results for the isosteric heat of adsorption, radial distribution function (O-O and O-H), hydrogen bond statistics and the cluster size distribution of water molecules are presented. The snapshots of GCMC simulations in CMK-3 and CMK-5 models show that the adsorption happens via the formation of water clusters. For the CMK-3 model, it was found that the pore filling occurred via the formation of a single water cluster and a few very small clusters. The water cluster size increased with an increase in pore size of the CMK-3 model. For the CMK-5 model, it was found that the adsorption first occurred in the inner porosity (via cluster formation). There was no adsorption of water in the outer porosity during the filling of the inner porosity. After the inner porosity was completely filled, the water begins to fill the outer porosity. Snapshots from GCMC simulations of the CMK-5 model clearly show that the water adsorption in the outer porosity occurs via the formation and growth of clusters and there was no formation of layers of water in the porosity as seen for nonpolar fluids like nitrogen.

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.