Shedding Light on Dark Chemical Matter: The Discovery of a SARS-CoV-2 Mpro Main Protease Inhibitor through Intensive Virtual Screening and In Vitro Evaluation.

The development of specific antiviral therapies targeting SARS-CoV-2 remains fundamental because of the continued high incidence of COVID-19 and limited accessibility to antivirals in some countries. In this context, dark chemical matter (DCM), a set of drug-like compounds with outstanding selectivity profiles that have never shown bioactivity despite being extensively assayed, appears to be an excellent starting point for drug development. Accordingly, in this study, we performed a high-throughput screening to identify inhibitors of the SARS-CoV-2 main protease (Mpro) using DCM compounds as ligands. Multiple receptors and two different docking scoring functions were employed to identify the best molecular docking poses. The selected structures were subjected to extensive conventional and Gaussian accelerated molecular dynamics. From the results, four compounds with the best molecular behavior and binding energy were selected for experimental testing, one of which presented inhibitory activity with a Ki value of 48 ± 5 µM. Through virtual screening, we identified a significant starting point for drug development, shedding new light on DCM compounds.

Extending MeCP2 interactome: canonical nucleosomal histones interact with MeCP2.

MeCP2 is a general regulator of transcription involved in the repression/activation of genes depending on the local epigenetic context. It acts as a chromatin regulator and binds with exquisite specificity to gene promoters. The set of epigenetic marks recognized by MeCP2 has been already established (mainly, cytosine modifications in CpG and CpA), as well as many of the constituents of its interactome. We unveil a new set of interactions for MeCP2 with the four canonical nucleosomal histones. MeCP2 interacts with high affinity with H2A, H2B, H3 and H4. In addition, Rett syndrome associated mutations in MeCP2 and histone epigenetic marks modulate these interactions. Given the abundance and the structural/functional relevance of histones and their involvement in epigenetic regulation, this new set of interactions and its modulating elements provide a new addition to the 'alphabet' for this epigenetic reader.

Influencia de la prescripción del sistema de medicina de empresa en la organización de las farmacias de las clínicas de Heredia y la Unión de Tres Ríos / Influence of the prescription of system of medicine of enterprise in the organization of the pharmacy of clinics of Heredia and the Union de Tres Ríos

El sistema de medicina de empresa fue creado como un Sistema de Asistencia Técnica-Médica exclusiva para los asegurados empleados de la Empresa, sus familiares, así como trabajadores pensionados de la misma. Las Farmacias de la Institución han sufrido alteraciones, ya que no estaban preparadas ni poseían los recursos antes mencionados para asumir el despacho de las recetas generadas por ésta modalidad de atención. Se estableció como premisa de investigación que el no cumplimiento de la Normas de Prescripción y de Utilización de los Servicios Farmacéuticos por parte del Sistema de Medicina de Empresa influye negativamente en la organización de los recursos citados de las farmacias que se estudiaron. Para el diagnóstico de la situación real de las Farmacias, se seleccionó una muestra estadística de 397 recetas de ambas clínicas a las que se le aplicó un instrumento de medición que permitió determinar el cumplimiento o no de las Normas de Prescripción, encontrándose que en la mayoría (72 por ciento) se cumple lo establecido y que solo un (28 por ciento) del total analizado, la norma no estaba completa, por esto se concluyó que la receta no es un factor determinante en la Organización de las Farmacias