In silico identification of potential inhibitors against shikimate dehydrogenase through virtual screening and toxicity studies for the treatment of tuberculosis

The present study attempts to identify the novel inhibitors of shikimate dehydrogenase (SD), the enzyme that catalyzes the fourth reaction in the shikimate pathway, through virtual screening and toxicity studies. Crystal structure of SD was obtained from Protein Data Bank (PDB ID 4P4G, 1.7 Å) and subjected to energy minimization and structure optimization. A total of 13,803 compounds retrieved from two public databases and used for the virtual screening based on physicochemical properties (Lipinski rule of five) and molecular docking analyses. A total of 26 compounds with good AutoDock binding energies values ranging between −12.03 and −8.33 kcal/mol was selected and further filtered for absorption distribution metabolism excretion and toxicity analyses (ADMET). In this, eight compounds were selected, which satisfied all the ADME and toxicity analysis properties. Three compounds with better AutoDock binding energies values (ZINC12135132, −12.03 kcal/mol; ZINC08951370, −10.04 kcal/mol; and ZINC14733847, 9.82 kcal/mol) were considered for molecular dynamic (MD) simulation and molecular generalized born surface area (MM-GBSA) analyses. The results of the analyses revealed that the two ligands (ZINC12135132 and ZINC08951370) had better inhibitory activities within their complexes, after the 50-ns MD simulation, which suggested that the complexes formed stable conformation. It is noteworthy that compounds identified by docking, MD simulation, and MM-GBSA methods could be a drug for tuberculosis which required further experimental validation

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Integration of virtual screening and susceptibility test to discover active-site subpocket-specific biogenic inhibitors of Helicobacter pylori shikimate dehydrogenase

Shikimate dehydrogenase (HpSDH) (EC 1.1.1.25) is a key enzyme in the shikimate pathway of Helicobacter pylori (H. pylori), which catalyzes the NADPH-dependent reversible reduction of 3-dehydroshikimate to shikimate. Targeting HpSDH has been recognized as an attractive therapeutic strategy against H. pylori infection. Here, the catalytic active site in the crystal structure of HpSDH in complex with its substrate NADPH and product shikimate was examined in detail; the site can be divided into three spatially separated subpockets that separately correspond to the binding regions of shikimate, NADPH dihydronicotinamide moiety, and NADPH adenine moiety. Subsequently, a cascading protocol that integrated virtual screening and antibacterial test was performed against a biogenic compound library to identify biologically active, subpocket-specific inhibitors. Consequently, five, eight, and six promising compounds for, respectively, subpockets 1, 2, and 3 were selected from the top-100 docking-ranked hits, from which 11 compounds were determined to have high or moderate antibacterial potencies against two reference H. pylori strains, with MIC range between 8 and 93 μg/mL. It is found that the HpSDH active site prefers to accommodate amphipathic and polar inhibitors that consist of an aromatic core as well as a number of oxygen-rich polar/charged substituents such as hydroxyl, carbonyl, and carboxyl groups. Subpockets 1- and 2-specific inhibitors exhibit a generally higher activity than subpocket 3-specific inhibitors. Molecular dynamics simulations revealed an intense nonbonded network of hydrogen bonds, π-π stacking, and van der Waals contacts at the tightly packed complex interfaces of active-site subpockets with their cognate inhibitors, conferring strong stability and specificity to these complex systems. Binding energetic analysis demonstrated that the identified potent inhibitors can target their cognate subpockets with an effective selectivity over noncognate ones

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Metanol como marcador de abuso en el consumo de alcohol en muestras forenses / Methanol as abuse alcohol marker in forensic samples

Se determinó la cantidad de metanol presente en muestras de personas categorizadas como abstemias, bebedores sociales y alcohólicos, por la técnica de cromatografía de gases con inyección por espacio de cabeza, con el propósito de utilizar el metanol como marcador de alcoholismo, en muestras provenientes de necropsias realizadas en el Servicio Médico Forense de la Ciudad de México. Se encontró una cantidad significativamente mayor de metanol en los grupos de alcohólicos estudiados, respecto al de los grupos de bebedores sociales y abstemios, existiendo, sin embargo, cierto traslape entre los distintos grupos estudiados. Por tanto, la sensibilidad del metanol como marcador de alcoholismo es relativamente baja; pero, puede ser utilizado como marcador de un episodio de abuso en el consumo de bebidas alcohólicas. Un análisis por regresión múltiple de los datos obtenidos, así como de datos personales y hallazgos biológicos presentes en las necropsias realizadas, confirmó que la concentración de metanol en sangre, está directamente relacionada con el consumo de etanol en alcohólicos y con la presencia de la esteatosis hepática, lo que prueba la validez del metanol como marcador de abuso en el consumo de bebidas alcohólicas (AU)

Methanol in post-mortem samples from alcoholic with and without ethanol present at the time of death, social drinkers and teetotallers were determined with gas chromatography with head space injection, to study the possibility of using methanol as an alcoholism marker in post-mortem samples. A methanol statistical significant difference was found between the alcoholics groups and the social drinkers and teetotallers groups, thus methanol can be used as alcoholism marker, but as there is some overlap in the determined methanol concentration between the studied groups, the sensitivity of methanol as alcoholism marker is low, and indicates more an abuse ethanol episode. A multiple regression analysis revealed that the factors which impact the methanol concentration the most are a fatty liver and the consumption of ethanol amongst alcoholics, while factors traditionally linked to alcoholism such as cirrhosis do not have an impact on the methanol concentration found (AU)ien