ALDH7A1 deficiency is an epileptic encephalopathy whose seizures respond to treatment with supraphysiological doses of pyridoxine. It arises as a result of damaging variants in ALDH7A1, a gene in the lysine catabolism pathway. α-Aminoadipic semialdehyde (α-AASA) and Δ1-piperideine-6-carboxylate (P6C), which accumulate because of the block in the lysine pathway, are diagnostic biomarkers for this disorder. Recently, it has been reported that 6-oxo-pipecolic acid (6-oxo-PIP) also accumulates in the urine, CSF and plasma of ALDH7A1-deficient individuals and that, given its improved stability, it may be a more suitable biomarker for this disorder. This study measured 6-oxo-PIP in urine from a cohort of 30 patients where α-AASA was elevated and showed that it was above the normal range in all those above 6 months of age. However, 6-oxo-PIP levels were within the normal range in 33% of the patients below 6 months of age. Levels increased with age and correlated with a decrease in α-AASA levels. Longitudinal analysis of urine samples from ALDH7A1-deficient patients who were on a lysine restricted diet whilst receiving supraphysiological doses of pyridoxine showed that levels of 6-oxo-PIP remained elevated whilst α-AASA decreased. Similar to α-AASA, we found that elevated urinary excretion of 6-oxo-PIP can also occur in individuals with molybdenum cofactor deficiency. This study demonstrates that urinary 6-oxo-PIP may not be a suitable biomarker for ALDH7A1 deficiency in neonates. However, further studies are needed to understand the biochemistry leading to its accumulation and its potential long-term side effects.
- MeSH
- Aldehyde Dehydrogenase deficiency genetics MeSH
- Biomarkers * urine MeSH
- Child MeSH
- Epilepsy urine MeSH
- Infant MeSH
- 2-Aminoadipic Acid urine analogs & derivatives MeSH
- Pipecolic Acids * urine MeSH
- Humans MeSH
- Lysine deficiency urine MeSH
- Aldehyde Dehydrogenase, Mitochondrial deficiency genetics MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Pyridoxine deficiency urine therapeutic use MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Male MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Drug repurposing requires a limited resource, cost-effective and faster method to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, this in silico studies attempts to identify the drug-likeness properties of ravidasvir, an II/III phase clinical trial chronic hepatitis C drug against 3-Chymotrypsin-like protease (3CLpro) of SARS-CoV-2 to combat the ongoing coronavirus disease 2019 (COVID-19) pandemic. This protease is predominantly involved in virus replication cycle; hence it is considered as a potent drug target. The molecular docking results showed that ravidasvir was found to be potent inhibitors of 3CLpro with scoring function based binding energy is -26.7 kJ/mol. Further dynamic behaviour of apo form and complex form of ravidasvir with 3CLpro were studied using molecular dynamics (MD) simulations over 500 ns each, total 2 μs time scale. The motion of the protein was studied using principal component analysis of the MD simulation trajectories. The binding free energy calculated using MM/PBSA method from the MD simulation trajectory was -190.3 ± 70.2 kJ/mol and -106.0 ± 26.7 kJ/mol for GROMOS96 54A7 and AMBER99SB-ILDN force field, respectively. This in silico studies suggesting ravidasvir might be a potential lead molecule against SARS-CoV-2 for further optimization and drug development to combat the life-threatening COVID-19 pandemic.Communicated by Ramaswamy H. Sarma.
- MeSH
- Adipates MeSH
- Benzimidazoles MeSH
- COVID-19 * MeSH
- Cysteine Endopeptidases chemistry MeSH
- COVID-19 Drug Treatment MeSH
- Protease Inhibitors chemistry MeSH
- Coronavirus 3C Proteases MeSH
- Humans MeSH
- Pandemics MeSH
- SARS-CoV-2 * MeSH
- Molecular Dynamics Simulation MeSH
- Molecular Docking Simulation MeSH
- Succinates MeSH
- Valine analogs & derivatives MeSH
- Viral Nonstructural Proteins chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Ricin is a potent cytotoxin with no available antidote. Its catalytic subunit, RTA, damages the ribosomal RNA (rRNA) of eukaryotic cells, preventing protein synthesis and eventually leading to cell death. The combination between easiness of obtention and high toxicity turns ricin into a potential weapon for terrorist attacks, urging the need of discovering effective antidotes. On this context, we used computational techniques, in order to identify potential ricin inhibitors among approved drugs. Two libraries were screened by two different docking algorithms, followed by molecular dynamics simulations and MM-PBSA calculations in order to corroborate the docking results. Three drugs were identified as potential ricin inhibitors: deferoxamine, leucovorin and plazomicin. Our calculations showed that these compounds were able to, simultaneously, form hydrogen bonds with residues of the catalytic site and the secondary binding site of RTA, qualifying as potential antidotes against intoxication by ricin.Communicated by Ramaswamy H. Sarma.
Metabolic profile of mephedrone (4-methylmethcathinone, 4-MMC), a frequently abused recreational drug, was determined in rats in vivo. The urine of rats dosed with a subcutaneous bolus dose of 20mg 4-MMC/kg was analysed by LC/MS. Ten phase I and five phase II metabolites were identified by comparison of their retention times and MS(2) spectra with those of authentic reference standards and/or with the MS(2) spectra of previously identified metabolites. The main metabolic pathway was N-demethylation leading to normephedrone (4-methylcathinone, 4-MC) which was further conjugated with succinic, glutaric and adipic acid. Other phase I metabolic pathways included oxidation of the 4-methyl group, carbonyl reduction leading to dihydro-metabolites and ω-oxidation at the position 3'. Five of the metabolites detected, namely, 4-carboxynormephedrone (4-carboxycathinone, 4-CC), 4-carboxydihydronormephedrone (4-carboxynorephedrine, 4-CNE), hydroxytolyldihydro-normephedrone (4-hydroxymethylnorephedrine, 4-OH-MNE) and conjugates of 4-MC with glutaric and adipic acid, have not been reported as yet. The last two conjugates represent a novel, hitherto unexploited, type of phase II metabolites in mammals together with an analogous succinic acid conjugate of 4-MC identified by Pozo et al. (2015). These conjugates might be potentially of great importance in the metabolism of other psychoactive amines.
- MeSH
- Adipates metabolism MeSH
- Chromatography, Liquid MeSH
- Glutarates metabolism MeSH
- Mass Spectrometry MeSH
- Rats MeSH
- Succinic Acid metabolism MeSH
- Dicarboxylic Acids metabolism MeSH
- Metabolome MeSH
- Methamphetamine analogs & derivatives chemistry toxicity urine MeSH
- Rats, Wistar MeSH
- Dose-Response Relationship, Drug MeSH
- Xenobiotics chemistry toxicity urine MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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- MeSH
- Adipates * pharmacology isolation & purification therapeutic use MeSH
- Anti-Bacterial Agents * pharmacology isolation & purification MeSH
- Diptera * MeSH
- Gram-Negative Bacteria growth & development drug effects MeSH
- Gram-Positive Bacteria growth & development drug effects MeSH
- Growth Inhibitors MeSH
- Klebsiella pneumoniae growth & development drug effects MeSH
- Larva MeSH
- Methicillin-Resistant Staphylococcus aureus growth & development drug effects MeSH
- Microbial Sensitivity Tests * statistics & numerical data MeSH
- Microbial Viability drug effects MeSH
- Shigella dysenteriae growth & development drug effects MeSH
- Staphylococcus aureus growth & development drug effects MeSH
- In Vitro Techniques MeSH
- Tissue Extracts pharmacology MeSH
- Chromatography, High Pressure Liquid statistics & numerical data MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
