RESUMO
Gap junctions (GJs) made of connexin-43 (Cx43) are necessary for the conduction of electrical impulses in the heart. Modulation of Cx43 GJ activity may be beneficial in the treatment of cardiac arrhythmias and other dysfunctions. The search for novel GJ-modulating agents using molecular docking allows for the accurate prediction of binding affinities of ligands, which, unfortunately, often poorly correlate with their potencies. The objective of this study was to demonstrate that a Quantitative Structure-Activity Relationship (QSAR) model could be used for more precise identification of potent Cx43 GJ inhibitors. Using molecular docking, QSAR, and 3D-QSAR, we evaluated 16 known Cx43 GJ inhibitors, suggested the monocyclic monoterpene d-limonene as a putative Cx43 inhibitor, and tested it experimentally in HeLa cells expressing exogenous Cx43. The predicted concentrations required to produce 50% of the maximal effect (IC50) for each of these compounds were compared with those determined experimentally (pIC50 and eIC50, respectively). The pIC50ies of d-limonene and other Cx43 GJ inhibitors examined by our QSAR and 3D-QSAR models showed a good correlation with their eIC50ies (R = 0.88 and 0.90, respectively) in contrast to pIC50ies obtained from molecular docking (R = 0.78). However, molecular docking suggests that inhibitor potency may depend on their docking conformation on Cx43. Searching for new potent, selective, and specific inhibitors of GJ channels, we propose to perform the primary screening of new putative compounds using the QSAR model, followed by the validation of the most suitable candidates by patch-clamp techniques.
RESUMO
Background and Objectives: Heart failure (HF) is a threatening health condition that is associated with an increasing prevalence and high expenses because of frequent patient hospitalizations. The purpose of this study was to evaluate the factors that influence the length of in-hospital stay in HF patients. Materials and Methods: A total of 220 patients (43.2% men), admitted to the Department of Cardiology, Kaunas Hospital of Lithuanian University of Health Sciences from the 1st of January 2021 to the 31st of May 2021, were included in this study. According to the length of in-hospital stay, patients were stratified into two groups: the first group's length of stay (LOS) was from 1 to 8 days, and the second group's LOS was 9 days or more. Results: The median LOS was 8 (6-10) days. Multivariate logistic regression analysis revealed five predictors as independent factors associated with prolonged hospitalization. These predictors included treatment interruption (OR 3.694; 95% CI 1.080-12.630, p = 0.037), higher value of NT-proBNP (OR 3.352; 95% CI 1.468-7.659, p = 0.004), estimated glomerular filtration rate (eGFR) ≤ 50 mL/min/1.73 m2 (OR 2.423; 95% CI 1.090-5.383, p = 0.030), systolic blood pressure (BP) ≤ 135 mmHg (OR 3.100; 95% CI 1.421-6.761, p = 0.004) and severe tricuspid valve regurgitation (OR 2.473; 95% CI 1.086-5.632, p = 0.031). Conclusions: Several variables were identified as significant clinical predictors for prolonged length of in-hospital stay in HF patients where treatment interruption, higher NT-proBNP value and lower systolic BP at admission were the most important.
