Synthesis, Spectral Study and Theoretical Treatment of 2-(2-(4-bromocyclohexa-1, 3-dienyl)-4-oxo-2H- benz [1, 3] oxazin-3(4H)-ylamino)-2-oxoethyl carbamimidothioate and Derivatives.

The standard heat of formation (ΔHof) and binding energy (ΔEb) for the free compound and their derivatives are calculated by using the PM3 method at 273K of Hyperchem.-8.07 program. The compound is more stable than their derivatives. furthermore to investigate the reactive site of the molecules the electrostatic potential of free derivatives is measured and pm3 is used to evaluate the vibrational spectra of the free derivatives, the frequencies are obtained approximately agreed with those values experimentally found; in addition, the calculation helps to assign clearly the most diagnostic bands .

Vibrational Spectroscopic and Molecular Docking Studies of Amrinone, a Cardiotonic Inotropic Drug-=SUP=-*-=/SUP=-

Amrinone is a class I cardiotonic inotropic agent, which is known to increase the cyclic adenosine monophosphate (cAMP) level by inhibiting the phosphodiesterase 3 (PDE3) enzyme. In this study the theoretically possible stable conformations of the amrinone, was examined first by conformational analysis method and then the obtained most stable conformation was optimized by DFT/wb97xd/6-311++G(d,p) level of theory using Gaussian 03 program. The credibility of the theoretical model was confirmed by comparison of experimental and theoretical vibrational spectra of the title molecule. The fundamental vibrational wavenumbers, IR and Raman intensities of the optimized structure of amrinone were determined using DFT/wb97xd/6-311++G(d,p) level of theory and compared with the experimental vibrational spectra. To investigate the influence of amrinone on cAMP enhancement, the docking simulations towards PDE3B were carried out and the main binding interactions of amrinone with PDE3 were elucidated. Cytochrome P450s (CYPs) are very important phase I metabolizing enzymes. The interaction between amrinone and CYPs (CYP1A2, CYP2C9 and CYP2C19) was investigated by docking simulations. Moreover, molecular docking of the title molecule with different proteins and receptors were studied to reveal potential mechanisms for therapeutic applications. Molecular docking simulations revealed that amrinone showed strong binding affinity to integrins α5β1 (Delta G=-6.6 kcal/mol) and αIIbβ3 (-6.6 kcal/mol), and DNA (-6.5 kcal/mol). The results correlated with its anticancer activity. The drug likeness and ADMET properties of amrinone were analyzed for the prediction of pharmacokinetic profiles. Key words: amrinone, DFT calculations, FTIR, Molecular Docking, ADMET.

Melting and Re-Freezing Leads to Irreversible Changes in the Morphology and Molecular-Level Dynamics of Pfizer-BioNTech COVID-19 Vaccine

Background and Objectives: As an mRNA-based vaccine, the Pfizer-BioNTech COVID-19 vaccine has stringent cold storage requirements to preserve functionality of the mRNA active ingredient. To this end, lipid components of the vaccine formulation play an important role in stabilizing and protecting the mRNA molecule for long-term storage. The purpose of the current study was to measure molecular-level dynamics as a function of temperature in the Pfizer-BioNTech COVID-19 vaccine to gain microscopic insight into its thermal stability. Materials and Methods: We used quasielastic and inelastic neutron scattering to probe (1) the vaccine extracted from the manufacturer-supplied vials and (2) unperturbed vaccine in the original manufacturer-supplied vials. The latter measurement was possible due to the high penetrative power of neutrons. Results: Upon warming from the low-temperature frozen state, the vaccine in its original form exhibits two-step melting, indicative of a two-phase morphology. Once the melting is completed (above 0 °C), vaccine re-freezing cannot restore its original two-phase state. This observation is corroborated by the changes in the molecular vibrational spectra. The molecular-level mobility measured in the resulting single-phase state of the re-frozen vaccine greatly exceeds the mobility measured in the original vaccine. Conclusions: Even a brief melting (above 0 °C) leads to an irreversible alteration of the two-phase morphology of the original vaccine formulation. Re-freezing of the vaccine results in a one-phase morphology with much increased molecular-level mobility compared to that in the original vaccine, suggesting irreversible deterioration of the vaccine’s in-storage stability. Neutron scattering can be used to distinguish between the vibrational spectra characteristic of the original and deteriorated vaccines contained in the unperturbed original manufacturer-supplied vials.

Molecular dynamics with constrained nuclear electronic orbital density functional theory: Accurate vibrational spectra from efficient incorporation of nuclear quantum effects

Nuclear quantum effects play a crucial role in many chemical and biological systems involving hydrogen atoms yet are difficult to include in practical molecular simulations. In this Letter, we combine our recently developed methods of constrained nuclear-electronic orbital density functional theory (cNEO-DFT) and constrained minimized energy surface molecular dynamics (CMES-MD) to create a new method for accurately and efficiently describing nuclear quantum effects in molecular simulations. Using this new method, dubbed cNEO-MD, the vibrational spectra of a set of small molecules are calculated and compared with those from conventional ab initio molecular dynamics (AIMD) as well as from experiments. With the same formal scaling, cNEO-MD greatly outperforms AIMD in describing the vibrational modes with significant hydrogen motion characters, demonstrating the promise of cNEO-MD for simulating chemical and biological systems with significant nuclear quantum effects.

Anharmonic Vibrational Frequencies of Water Borane and Associated Molecules

Water borane (BH3OH2) and borinic acid (BH2OH) have been proposed as intermediates along the pathway of hydrogen generation from simple reactants: water and borane. However, the vibrational spectra for neither water borane nor borinic acid has been investigaged experimentally due to the difficulty of isolating them in the gas phase, making accurate quantum chemical predictions for such properties the most viable means of their determination. This work presents theoretical predictions of the full rotational and fundamental vibrational spectra of these two potentially application-rich molecules using quartic force fields at the CCSD(T)-F12b/cc-pCVTZ-F12 level with additional corrections included for the effects of scalar relativity. This computational scheme is further benchmarked against the available gas-phase experimental data for the related borane and HBO molecules. The differences are found to be within 3 cm−1 for the fundamental vibrational frequencies and as close as 15 MHz in the B0 and C0 principal rotational constants. Both BH2OH and BH3OH2 have multiple vibrational modes with intensities greater than 100 km mol−1, namely ν2 and ν4 in BH2OH, and ν1, ν3, ν4, ν9, and ν13 in BH3OH2. Finally, BH3OH2 has a large dipole moment of 4.24 D, which should enable it to be observable by rotational spectroscopy, as well.