Novel coronavirus disease 2019 (COVID-19) has resulted in a global pandemic and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several studies have suggested that a precise disulfide-thiol balance is crucial for viral entry and fusion into the host cell and that oxidative stress generated from free radicals can affect this balance. Here, we reviewed the current knowledge about the role of oxidative stress on SARS-CoV and SARS-CoV-2 infections. We focused on the impact of antioxidants, like NADPH and glutathione, and redox proteins, such as thioredoxin and protein disulfide isomerase, that maintain the disulfide-thiol balance in the cell. The possible influence of these biomolecules on the binding of viral protein with the host cell angiotensin-converting enzyme II receptor protein as well as on the severity of COVID-19 infection was discussed.

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an ongoing pandemic of coronavirus disease (COVID-19), which started in 2019. This is a member of Coronaviridae family in the genus Betacoronavirus, which also includes SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). The angiotensinconverting enzyme 2 (ACE2) is the functional receptor for SARS-CoV and SARS-CoV-2 to enter the host cells. In particular, the interaction of viral spike proteins with ACE2 is a critical step in the viral replication cycle. The receptor-binding domain of the viral spike proteins and ACE2 have several cysteine residues. In this study, the role of thiol−disulfide balance on the interactions between SARS-CoV/CoV-2 spike proteins and ACE2 was investigated using molecular dynamics simulations. The study revealed that the binding affinity was significantly impaired when all of the disulfide bonds of both ACE2 and SARS-CoV/CoV-2 spike proteins were reduced to thiol groups. The impact on the binding affinity was less severe when the disulfide bridges of only one of the binding partners were reduced to thiols. This computational finding possibly provides a molecular basis for the differential COVID-19 cellular recognition due to the oxidative stress.

Metallic radionuclides are the mainstay of both diagnostic and therapeutic radiopharmaceuticals. Therapeutic nuclear medicine is less advanced but has tremendous potential if the radionuclide is accurately targeted. Great interest exists in the field of inorganic chemistry for developing target specific radiopharmaceuticals based on radiometals for non-invasive disease detection and cancer radiotherapy. This perspective will focus on the nuclear properties of a few important radiometals and their recent applications to developing radiopharmaceuticals for imaging and therapy. Other topics for discussion will include imaging techniques, radiotherapy, analytical techniques, and radiation safety. The ultimate goal of this perspective is to introduce inorganic chemists to the field of nuclear medicine and radiopharmaceutical development, where many applications of fundamental inorganic chemistry can be found.

Flavin adenine dinucleotide (FAD) is a common cofactor in redox proteins, and its reduction potentials are controlled by the protein environment. This regulation is mainly responsible for the versatile catalytic functions of flavoenzymes. In this article, we report computations of the reduction potentials of FAD in medium-chain acyl-CoA dehydrogenase (MCAD) and cholesterol oxidase (CHOX). In addition, the reduction potentials of lumiflavin in aqueous solution have also been computed. Using molecular dynamics and free-energy perturbation techniques, we obtained the free-energy changes for two-electron/two-proton as well as one-electron/one-proton addition steps. We employed a combined quantum mechanical and molecular mechanical (QM/MM) potential, in which the flavin ring was represented by the self-consistent-charge density functional tight-binding (SCC-DFTB) method, while the rest of the enzyme-solvent system was treated by classical force fields. The computed two-electron/two-proton reduction potentials for lumiflavin and the two enzyme-bound FADs are in reasonable agreement with experimental data. The calculations also yielded the pKa values for the one-electron reduced semiquinone (FH*) and the fully reduced hydroquinone (FH2) forms. The pKa of the FAD semiquinone in CHOX was found to be around 4, which is 4 units lower than that in the enzyme-free state and 2 units lower than that in MCAD; this supports the notion that oxidases have a greater ability than dehydrogenases to stabilize anionic semiquinones. In MCAD, the flavin ring interacts with four hydrophobic residues and has a significantly bent structure, even in the oxidized state. The present study shows that this bending of the flavin imparts a significant destabilization (approximately 5 kcal/mol) to the oxidized state. The reduction potential of lumiflavin was also computed using DFT (M06-L and B3LYP functionals with 6-31+G(d,p) basis set) with the SM6 continuum solvation model, and the results are in good agreement with results from explicit free-energy simulations, which supports the conclusion that the SCC-DFTB/MM computation is reasonably accurate for both 1e(-)/1H+ and 2e(-)/2H+ reduction processes. These results suggest that the first coupled electron-proton addition is stepwise for both the free and the two enzyme-bound flavins. In contrast, the second coupled electron-proton addition is also stepwise for the free flavin but is likely to be concerted when the flavin is bound to either the dehydrogenase or the oxidase enzyme.

F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy.

Prolyl-tRNA synthetases (ProRSs) have been shown to activate both cognate and some noncognate amino acids and attach them to specific tRNAPro substrates. For example, alanine, which is smaller than cognate proline, is misactivated by Escherichia coli ProRS. Mischarged Ala-tRNAPro is hydrolyzed by an editing domain (INS) that is distinct from the activation domain. It was previously shown that deletion of the INS greatly reduced cognate proline activation efficiency. In the present study, experimental and computational approaches were used to test the hypothesis that INS deletion alters the internal protein dynamics leading to reduce catalytic function. Kinetic studies with two ProRS variants, G217A and E218A, revealed decreased amino acid activation efficiency. Molecular dynamics studies showed motional coupling between the INS and protein segments containing the catalytically important proline-binding loop (PBL, residues 199–206). In particular, the complete deletion of INS, as well as mutation of G217 or E218 to alanine, exhibited significant effects on the motion of the PBL. The presence of coupled-dynamics between neighboring protein segments was also observed through in silico mutations and essential dynamics analysis. Taken together, the present study demonstrates that structural elements at the editing domain-activation domain interface participate in coupled motions that facilitate amino acid binding and catalysis by bacterial ProRSs, which may explain why truncated or defunct editing domains have been maintained in some systems, despite the lack of catalytic activity.

The mononuclear oxovanadium complexes [V V OL(OR)] (R: Me, 1a; Et, 1b; Pr i , 1c) and [V IV OLB] (B: Im, 2a; BzIm, 2b) of the tridentate ONS donor ligand S-methyl 3-((2-hydroxyphenyl)methyl)dithiocarbazate (H 2 L) are reported. The novel mixed-valence (µ-oxo)divanadium(IV,V) complex (BzImH)[(LVO) 2 O] (3) was synthesized using 1a and 2b as precursors. All of the complexes were characterized by various physical techniques, including 1 H NMR, EPR, and cyclic voltammetry. The X-ray structures of 1a and 3 were determined. Crystals of 1a are triclinic, of space group P1 h, with a ) 11.045(1) Å, b ) 13.429(4) Å, c ) 9.611(1) Å, R ) 100.00(1)°, β ) 114.33(1)°, γ ) 81.00(1)°, and Z ) 4. The asymmetric unit of 1a contains two independent molecules with minor conformational differences. Crystals of 3 are monoclinic, of space group P2 1 /n, with a ) 10.10(1) Å, b ) 20.594(9) Å, c ) 14.679(8) Å, β ) 95.28(6)°, and Z ) 4. 3 is a bent molecule, with a V-O-V bridge angle of 144.0(6)°. It has a trapped-valence structure in the solid state with a rare syn-dioxo-µ-oxo [OV-O-VO] 3+ core and reveals a 15-line EPR spectrum ( 51 V, I ) 7 / 2 ) in solution (CH 3 CN) at room temperature, indicating delocalization of the odd electron. The spectrum gradually changes its profile with the lowering of temperature and ultimately collapses into an 8-line pattern at 225 K due to thermal trapping of the odd electron (k th ∼ 7.3 × 10 9 s -1 ). 3 also exhibits an intervalence transfer (IT) band in solution with features (λ max 970 nm, 1670 M -1 cm -1 in CH 3 CN) remaining practically unaffected by the change of solvents. The IT band was analyzed by Gaussian curve fitting, and the electron exchange integral H AB was estimated as 2210 cm -1 . Thus, 3 appears to be an interesting mixed-oxidation-state (µ-oxo)divanadium(IV,V) complex that exhibits a trapped-valence structure in the solid state and undergoes valence delocalization in solution.

Zinc(II) and copper(II) complexes of two new potentially pentadentate ligands based on methyl 2-aminocyclopent-1-ene-1-dithiocarboxylate with pendent pyrazolyl groups (Me 2 pzCH 2 ) 2 NC 2 H 3 RNHC 5 H 6 CSSCH 3 (R ) H, Hmmecd, and R ) CH 3 , Hmmpcd, both having N 4 S donor atoms set) have been reported. The molecular structures of [Zn(mmpcd)]ClO 4 (1b) and [Cu(mmpcd)]ClO 4 (2b) show a distorted trigonal bipyramidal geometry for the Zn(II) ion and a square pyramidal geometry for the Cu(II) ion. 1b crystallizes in the triclinic space group P1 h, a ) 9.900(3) Å, b ) 15.379(5) Å, c ) 8.858(2) Å, R ) 99.93(2)°, β ) 93.62(2)°, γ ) 100.38(2)°, V ) 1300.5(7) Å 3 , and Z ) 2; while 2b crystallizes in the monoclinic space group P2 1 /n, a ) 12.859(6) Å, b ) 12.642(3) Å, c ) 16.503(2) Å, β ) 102.67(2)°, V ) 2617(1) Å 3 , and Z ) 4. The structures were refined to final R ) 0.042 for 1b and 0.049 for 2b. The EPR and electronic spectroscopic studies showed that the copper(II) species doped into zinc(II) complex adopts the zinc(II) trigonal bipyramidal structure. The cyclic voltammetric measurements indicated one-electron reversible reduction of the copper(II) complex occurring at -0.74 V, while irreversible oxidation to copper (III) takes place at +0.75 V (Vs Ag/AgNO 3 ).