Identification of phytocompounds from Houttuynia cordata Thunb. as potential inhibitors for SARS-CoV-2 replication proteins through GC–MS/LC–MS characterization,molecular docking and molecular dynamics simulation

The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a massive viral disease outbreak of international concerns. The present study is mainly intended to identify the bioactive phytocompounds from traditional antiviral herb Houttuynia cordata Thunb. as potential inhibitors for three main replication proteins of SARS-CoV-2, namely Main protease (Mpro), Papain-Like protease (PLpro) and ADP ribose phosphatase (ADRP) which control the replication process. A total of 177 phytocompounds were characterized from H. cordata using GC–MS/LC–MS and they were docked against three SARS-CoV-2 proteins (receptors), namely Mpro, PLpro and ADRP using Epic, LigPrep and Glide module of Schrödinger suite 2020-3. During docking studies, phytocompounds (ligand) 6-Hydroxyondansetron (A104) have demonstrated strong binding affinity toward receptors Mpro (PDB ID 6LU7) and PLpro (PDB ID 7JRN) with G-score of???7.274 and???5.672, respectively, while Quercitrin (A166) also showed strong binding affinity toward ADRP (PDB ID 6W02) with G-score -6.788. Molecular Dynamics Simulation (MDS) performed using Desmond module of Schrödinger suite 2020–3 has demonstrated better stability in the ligand–receptor complexes A104-6LU7 and A166-6W02 within 100 ns than the A104-7JRN complex. The ADME-Tox study performed using SwissADMEserver for pharmacokinetics of the selected phytocompounds 6-Hydroxyondansetron (A104) and Quercitrin (A166) demonstrated that 6-Hydroxyondansetron passes all the required drug discovery rules which can potentially inhibit Mpro and PLpro of SARS-CoV-2 without causing toxicity while Quercitrin demonstrated less drug-like properties but also demonstrated as potential inhibitor for ADRP. Present findings confer opportunities for 6-Hydroxyondansetron and Quercitrin to be developed as new therapeutic drug against COVID-19.

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Dual Fluorometric Detection of Fe3+ and Hg2+ Ions in an Aqueous Medium Using Carbon Quantum Dots as a “Turn-off” Fluorescence Sensor

The present study aimed to develop a carbon dots-based fluorescence (FL) sensor that can detect more than one pollutant simultaneously in the same aqueous solution. The carbon dots-based FL sensor has been prepared by employing a facile hydrothermal method using citric acid and ethylenediamine as precursors. The as-synthesized CDs displayed excellent hydrophilicity, good photostability and blue fluorescence under UV light. They have been used as an efficient “turn-off” FL sensor for dual sensing of Fe³⁺ and Hg²⁺ ions in an aqueous medium with high sensitivity and selectivity through a static quenching mechanism. The lowest limit of detection (LOD) for Fe³⁺ and Hg²⁺ ions was found to be 0.406 µM and 0.934 µM, respectively over the concentration range of 0-50 µM. Therefore, the present work provides an effective strategy to monitor the concentration of Fe³⁺ and Hg²⁺ ions simultaneously in an aqueous medium using environment-friendly CDs.

Graphical Abstract

     

Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP

The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The P. falciparum DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit E. coli DegP protease activity. To identify novel potential inhibitors specific to PfDegP allosteric and the catalytic binding sites, we performed a high throughput in silico screening using Malaria Box, Pathogen Box, Maybridge library, ChEMBL library and the library of FDA approved compounds. The screening helped identify five best binders that showed high affinity to PfDegP allosteric (T0873, T2823, T2801, {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, CD00811) and the catalytic binding site (T0078L, T1524, T2328, BTB11534 and 552691). Further, molecular dynamics simulation analysis revealed {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, BTB11534 as the best hits forming a stable complex. WaterMap and electrostatic complementarity were used to evaluate the novel bio-isosteric chemotypes of {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, that led to the identification of 231 chemotypes that exhibited better binding affinity. Further analysis of the top 5 chemotypes, based on better binding affinity, revealed that the addition of electron donors like nitrogen and sulphur to the side chains of butanoate group are more favoured than the backbone of butanoate group. In a nutshell, the present study helps identify novel, potent and Plasmodium specific inhibitors, using high throughput in silico screening and bio-isosteric replacement, which may be experimentally validated.     

Validated Stability-Indicating Method for Alendronate Sodium Employing Zwitterionic Hydrophilic Interaction Chromatography Coupled with Charged Aerosol Detection

Alendronate sodium is widely used in the treatment of osteoporosis and Paget’s disease. The HPLC method development for alendronate sodium, in particular, is challenging owing to the absence of chromophoric group and its high polarity. In the present study, a short and simple isocratic method was developed involving hydrophilic interaction liquid chromatography, coupled with a charged aerosol detector. The developed method was validated according to the ICH Q2(R1) guideline and was successfully applied for the analysis of a marketed formulation containing the drug.

     

Reversed Temperature-Dependent Propagation Delay Characteristics in Nanometer CMOS Circuits

The supply voltage to threshold voltage ratio is reduced with each new technology generation. The gate overdrive variation with temperature plays an increasingly important role in determining the speed characteristics of CMOS integrated circuits. The temperature-dependent propagation delay characteristics, as shown in this brief, will experience a complete reversal in the near future. Contrary to the older technology generations, the speed of circuits in a 45-nm CMOS technology is enhanced when the temperature is increased at the nominal supply voltage. Operating an integrated circuit at the prescribed nominal supply voltage is not preferable for reliable operation under temperature fluctuations. A design methodology based on optimizing the supply voltage for temperature-variation-insensitive circuit performance is proposed in this brief. The optimum supply voltage is 45% to 53% lower than the nominal supply voltage in a 180-nm CMOS technology. Alternatively, the optimum supply voltage is 15% to 35% higher than the nominal supply voltage in a 45-nm CMOS technology. The speed and energy tradeoffs in the supply voltage optimization technique are also presented     

A short note on the entrainment and exit boundary conditions

An attempt is made to find out the suitable entrainment and exit boundary conditions in laminar flow situations. Streamfunction vorticity formulation of the Navier–Stokes equations are solved by ADI method. Two‐dimensional laminar plane wall jet flow is used to test different forms of the boundary conditions. Results are compared with the experimental and similarity solution and the proper boundary condition is suggested. The Kind 1 boundary condition is recommended. It consists of zero first derivative condition for velocity variable and for streamfunction equation, mixed derivative at the entrainment and exit boundaries. Copyright © 2005 John Wiley & Sons, Ltd.     

Hydroxyl ion conduction in ytterbium-doped strontium cerate at T<580 K in H2O/air atmosphere

Open circuit voltage (OCV) measurements in H₂O/air concentration cells at T<580 K using Yb-doped SrCeO₃ electrolyte indicate that under these conditions, protons are transported through the electrolyte as -ve ions, possibly as hydroxyl (OH⁻) ions. The H⁺ ionic transport, which is generally reported, becomes the dominant mode for H₂O/air concentration cells at temperatures greater than 750 K or when H₂O/air electrodes are replaced by H₂/Ar, and the anomalous OCV sign disappears. The combination of low temperature and the presence of hydrogen and oxygen as provided by the H₂O/air system appears to be necessary for the postulated hydroxyl ion electrode reactions to take place. In addition to OCV measurements, results from impedance spectroscopy are used to provide evidence in support of the suggested hydroxyl ion mode of protonic transport under the specified conditions. These findings are directly relevant in the development of novel humidity sensors in the temperature range 450–580K and is reported in a separate paper in this conference. Paper presented at the 3rd Euroconference on Solid State Ionics, Teulada, Sardinia, Italy, Sept. 15–22, 1996