RESUMO
Targeting RNA including viral RNAs with small molecules is an emerging field. The hepatitis C virus internal ribosome entry site (HCV IRES) is a potential target for translation inhibitor development to raise drug resistance mutation preparedness. Using RNA-focused and unbiased molecule libraries, a structure-based virtual screening (VS) by molecular docking and pharmacophore analysis was performed against the HCV IRES subdomain IIa. VS hits were validated by a microscale thermophoresis (MST) binding assay and a Förster resonance energy transfer (FRET) assay elucidating ligand-induced conformational changes. Ten hit molecules were identified with potencies in the high to medium micromolar range proving the suitability of structure-based virtual screenings against RNA-targets. Hit compounds from a 2-guanidino-quinazoline series, like the strongest binder, compound 8b with an EC50 of 61 µM, show low molecular weight, moderate lipophilicity and reduced basicity compared to previously reported IRES ligands. Therefore, it can be considered as a potential starting point for further optimization by chemical derivatization.
RESUMO
Objectives: We explored the effects of a mindfulness program based on the satipatthana sutta (instead of a contemporary Western program), with participants as collaborators, using a single-case experimental design. The main question was whether such a training has positive effects and, if so, whether and how the effects vary across participants and measures. Method: Participants chose the design (multiple baseline) and the measures to be repeatedly collected. Then they took part in a 6-week mindfulness training based on the satipatthana sutta; finally, they performed a preliminary data analysis of their own results. Reported are a selection of the visual analyses, intraindividual effect sizes (Tau-U), and the results of single-case meta-analyses over participants, as well as a multivariate graphical analysis of interindividual differences. Results: Substantial training effects were found on average and for the majority of participants for concentration, mind wandering, decentering, positive affect, and well-being. Effects were small for negative affect, and no effects were found for emotion regulation. However, interindividual variation was high, both in respect to specific measures and concerning the overall effect of the training program. Participants' motivation was found to be very high throughout the study. Conclusion: Our findings indicate that a traditional mindfulness program yields effects that are roughly comparable to the effects of secular mindfulness training regimens. Regarding participants as collaborators appears to have a strong motivating effect. And finally, the study demonstrates that using single-case experimental designs (instead of group designs) allows for a more fine-grained analysis of meditation effects. The high interindividual variation points to the possibility that the amount of unexplained variance in group studies is severely underestimated. Results from studies like the current one could have benefits for both theoretical advancement and custom-tailored assignment of specific forms of meditation to specific people with specific aims. Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-023-02160-1.
