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Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore = -13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = -9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC

Recent times witnessed an upsurge in the number of COVID cases which is primarily attributed to the emergence of several omicron variants, although there is substantial population vaccination coverage across the globe. Currently, many therapeutic antibodies have been approved for emergency usage. The present study critically evaluates the effect of mutations observed in several omicron variants on the binding affinities of different classes of RBD-specific antibodies using a combined approach of immunoinformatics and binding free energy calculations. Our binding affinity data clearly show that omicron variants achieve antibody escape abilities by incorporating mutations at the immunogenic hotspot residues for each specific class of antibody. K417N and Y505H point mutations are primarily accountable for the loss of class I antibody binding affinities. The K417N/Q493R/Q498R/Y505H combined mutant significantly reduces binding affinities for all the class I antibodies. E484A single mutation, on the other hand, drastically reduces binding affinities for most of the class II antibodies. E484A and E484A/Q493R double mutations cause a 33-38% reduction in binding affinity for the approved therapeutic monoclonal antibodies, Bamlanivimab (LY-CoV555). The Q498R RBD mutation observed across all the omicron variants can reduce ~12% binding affinity for REGN10987, a class III therapeutic antibody, and the L452R/Q498R double mutation causes a ~6% decrease in binding affinities for another class III therapeutic antibody, LY-CoV1404. Our data suggest that achieving the immune evasion abilities appears to be the selection pressure behind the emergence of omicron variants.

Acquiring the human ACE2 receptor usage trait enables the coronaviruses to spill over to humans. However, the origin of the ACE2 usage trait in coronaviruses is poorly understood. Using a multi-disciplinary approach combining evolutionary bioinformatics and molecular dynamics simulation, we decode the principal driving force behind human ACE2 receptor recognition in coronaviruses. Genomic content, evolutionary divergence, and codon usage bias analysis reveal that SARS-CoV2 is evolutionarily divergent from other human ACE2-user CoVs, indicating that SARS-CoV2 originates from a different lineage. Sequence analysis shows that all the human ACE2-user CoVs contain two insertions in the receptor-binding motif (RBM) that directly interact with ACE2. However, the insertion sequences in SARS-CoV2 are divergent from other ACE2-user CoVs, implicating their different recombination origins. The potential of mean force calculations reveals that the high binding affinity of SARS-CoV2 RBD to human ACE2 is primarily attributed to its ability to form a higher number of hydrogen bonds than the other ACE2-user CoVs. The adaptive branch-site random effects likelihood method identifies positive selection bias across the ACE2 user CoVs lineages. Recombination and selection forces shape the spike evolution in human ACE2-using beta-CoVs to optimize the interfacial hydrogen bonds between RBD and ACE2. However, these evolutionary forces work within the constraints of nucleotide composition, ensuring optimum codon adaptation of the spike (S) gene within the host cell.

Temperature dependent Raman spectra of a Dy@C82 thin film are investigated between 80 and 300 K. The first order temperature coefficient is evaluated for both Dy–C and C–C vibrational modes which reveals the presence of thermal and anharmonic contributions to the phonon hardening at low temperatures. The Dy–C mode broadens while decreasing the temperature revealing that the electron–phonon coupling is dominant over phonon–phonon coupling at low temperatures. In addition, laser-power dependent Raman spectra of Dy@C82 and Gd@C82 have been analyzed for estimating their first order power coefficients and the thermal conductivities.

We present a Raman spectroscopy investigation of the vibrational properties of a rare-earth endohedral metallofullerene, Gd@C82, at low temperatures. While lowering the temperature, the Raman spectra show a blueshift in the Gd–C and C–C vibrational modes which are attributed to both anharmonic and thermal expansion contributions in the fullerene cage. The experimental data are compared with the theories of the shift and broadening of the phonon lines, and respective anharmonic and temperature coefficients are evaluated. In addition, the force constant of the Gd–C82 vibration is derived at various temperatures using a linear harmonic oscillator model. No change in the oxidation state of the ion is noted in the examined temperature range.

We report magnetic properties of transition metal (TM) doped ZnO nanoparticles and compare the doping effects of different transition metal ions into the ZnO matrix. Stoner–Wohlfarth model has been used to study the switching behavior of magnetic moments by observing energy diagram and hysteresis. Low magnetic anisotropy in Zn1-xMxO nanoparticles is observed where M=Fe, Co, Ni and x is the dopant amount. We have considered chemical precipitation technique for the preparation of Zn1-xMxO samples and have compared the reversal processes of magnetic moments with respect to time in the nanoparticles.

We present temperature, laser power, and pressure dependent Raman spectral analysis of C 60 oxide (C 60O) thin films prepared by the photolysis method. The first order temperature, laser power, and pressure coefficients of the Raman frequencies are evaluated and are utilized for evaluating the thermal conductivity of C 60O. Its thermal conductivity is found to be 0.7 W m − 1 K − 1 which is marginally higher than that of bulk C 60. Raman frequencies corresponding to C–O and C–C bonds blueshift with a decrease in temperature which is attributed to the thermal contraction of C 60O molecules. The density functional measurements have been performed to optimize C 60O structure. The contraction in the C–O bond length has been corroborated with the experimental Raman shifts at different temperatures and is used to evaluate the linear expansion coefficient of C 60O. Pressure induced compression and polymerization of C 60O clusters are also illustrated. This study highlights the interplay between thermal and mechanical transformations in the C 60O cluster which may regulate its thermoelectric properties by tuning the intermolecular interactions.