Comparative molecular docking and simulation analysis of molnupiravir and remdesivir with SARS-CoV-2 RNA dependent RNA polymerase (RdRp)

Treatment of SARS-CoV-2 targeting its RNA dependent RNA polymerase (RdRp) is of current interest. Remdesivir has been approved for the treatment of COVID-19 around the world. However, the drug has been linked with pharmacological limitations like adverse effects and reduced efficiency. Nevertheless, recent advancements have depicted molnupiravir as an effective therapeutic agent to target the SARS-CoV-2 RdRp. The drug has cleared both in vitro and in vivo screening. It is in phase-III clinical trial. Nonetheless, there are no data on themolecular binding interaction of molnupiravir with RdRp. Therefore, it is of interest to report the binding interaction of molnupiravir using molecular docking. It is also of interest to show its stability during interaction using molecular dynamics and binding free energy calculations along with drug likeliness and pharmacokinetic properties in comparison with remdesivir.     

Lactation influences the serum level of leptin and growth hormone during the daily bathyphase in ewes

The aim of the study was to investigate the influence of early lactation on leptin and growth hormone (GH) during bathyphase. Forty lactating Sarda ewes were divided into two equal groups on the basis of their milk production levels: HIGH (>1100 g/day) and LOW (<900 g/day). From the 5th to the 110th day after lambing, every 15 days, body condition score (BCS) was recorded and milk samples were collected. At the same data point, blood sampling was performed and leptin, GH and, Non-Esterified Fatty Acids (NEFA) were assessed. On milk, fat and proteins were determined. Statistical differences were observed in BCS, leptin, GH, NEFA and fat concentration in milk between the two groups. BCS was lower in high group and decreased from the 20th to the 90th day of lactation. Leptin was higher in low group and increased from the 50th and the 65th day of lactation, in low and high groups, respectively. GH and NEFA were higher in high group and decreased from the mild lactation. In high group, BCS and milk yield were negatively correlated and leptin was negatively correlated with GH and NEFA. In low group, leptin was positively correlated with BCS and negatively correlated with the all studied parameters. GH and NEFA were positively correlated with both groups. In conclusion, milk yield had an effect on the leptin and GH plasma values recorded during their bathyphase.     

Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity during Working Memory Performance

Background

Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known.

Methods

Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [¹²³I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [¹²³I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory.

Results

Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [¹²³I]IBZM and of [¹²³I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT.

Conclusions

Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.