Coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused due to new coronavirus infection with 3 716075 deaths across the world as reported by the World Health Organization (WHO). SARS-CoV-2 main protease (M pro) plays a vital role in the replication of coronavirus and thus an attractive target for the screening of inhibitors for the therapy of COVID-19. The preclinical drugs ebselen and PX-12 are potent inhibitors of SARS-CoV-2 M pro and covalently modifies the active site Cys-145 residue of M pro through selenosulfide/disulfide. In the current report, using virtual screening methods, reactive sulfur species allicin is subjecting for covalent docking at the active site of SARS-CoV-2 M pro using PX-12 as a benchmark reference compound. The results indicate that allicin induces dual S-thioallylation of Cys-145 and Cys-85/ Cys-156 residues of SARS-CoV-2 M pro. Using density functional theory (DFT), Gibbs free energy change (DG) is calculated for the putative reactions between Nacetylcysteine amide thiol and allicin/allyl sulfenic acid. The overall reaction is exergonic and allyl disulfide of Cys-145 residue of M pro is involved in a sulfur mediated hydrogen bond. The results indicate that allicin causes dual S-thioallylation of SARS-CoV-2 M pro which may be of interest for treatment and attenuation of ongoing coronavirus infection.
The tetrapeptides Li504 and Li520, differing in the modification of the 4trans-hydroxylation of proline, are novel conopeptides derived from the venom duct transcriptome of the marine cone snail Conus lividus. These predicted mature peptides are homologous to the active site motif of oxidoreductases that catalyze the oxidation, reduction, and rearrangement of disulfide bonds in peptides and proteins. The estimated reduction potential of the disulfide of Li504 and Li520 is within the range of disulfide reduction potentials of oxidoreductases, indicating that they may catalyze the oxidative folding of conotoxins. Conformational features of Li504 and Li520 include the trans configuration of the Cys1−Pro2/Hyp2 peptide bond with a type 1 turn that is similar to the active site motif of glutaredoxin that regulates the oxidation of cysteine thiols to disulfides. Li504-and Li520-assisted oxidative folding of α-conotoxin ImI confirms that Li520 improves the yield of the natively folded peptide by concomitantly decreasing the yield of the non-native disulfide isomer and thus acts as a miniature disulfide isomerase. The geometry of the Cys1−Hyp2 peptide bond of Li520 shifts between the trans and cis configurations in the disulfide form and thiol/thiolate form, which regulates the deprotonation of the N-terminal cysteine residue. Hydrogen bonding of the hydroxyl group of 4-trans-hydroxyproline with the interpeptide chain unit in the mixed disulfide form may play a vital role in shifting the geometry of the Cys1−Hyp2 peptide bond from cis to trans configuration. The Li520 conopeptide together with similar peptides derived from other species may constitute a new family of "redox-active" conopeptides that are integral components of the oxidative folding machinery of conotoxins.
The products of the
Friedlander reaction, i.e., 1,8-naphthyridines,
have far-reaching impacts in materials science, chemical biology,
and medicine. The reported synthetic methodologies elegantly orchestrate
the diverse synthetic routes of naphthyridines but require harsh reaction
conditions, organic solvents, and expensive metal catalysts. Here,
we introduce gram-scale synthesis of 1,8-naphthyridines in water using
an inexpensive and biocompatible ionic liquid (IL) as a catalyst.
This is the first-ever report on the synthesis of naphthyridines in
water. This is a one-step reaction, and the product separation is
relatively easy. The choline hydroxide (ChOH) is used as a metal-free,
nontoxic, and water-soluble catalyst. In comparison to other catalysts
reported in the literature, ChOH has the advantage of forming an additional
hydrogen bond with the reactants, which is the vital step for the
reaction to happen in water. Density functional theory (DFT) and noncovalent
interaction (NCI) plot index analysis provide the plausible reaction
mechanism for the catalytic cycle and confirm that hydrogen bonds
with the IL catalyst are pivotal to facilitate the reaction. Molecular
docking and molecular dynamics (MD) simulations are also performed
to demonstrate the potentialities of the newly synthesized products
as drugs. Through MD simulations, it was established that the tetrahydropyrido
derivative of naphthyridine (10j) binds to the active
sites of the ts3 human serotonin transporter (hSERT) (PDB ID: 6AWO) without perturbing
the secondary structure, suggesting that 10j can be a
potential preclinical drug candidate for hSERT inhibition and depression
treatment.
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