SolPredictor: Predicting Solubility with Residual Gated Graph Neural Network.

Computational methods play a pivotal role in the pursuit of efficient drug discovery, enabling the rapid assessment of compound properties before costly and time-consuming laboratory experiments. With the advent of technology and large data availability, machine and deep learning methods have proven efficient in predicting molecular solubility. High-precision in silico solubility prediction has revolutionized drug development by enhancing formulation design, guiding lead optimization, and predicting pharmacokinetic parameters. These benefits result in considerable cost and time savings, resulting in a more efficient and shortened drug development process. The proposed SolPredictor is designed with the aim of developing a computational model for solubility prediction. The model is based on residual graph neural network convolution (RGNN). The RGNNs were designed to capture long-range dependencies in graph-structured data. Residual connections enable information to be utilized over various layers, allowing the model to capture and preserve essential features and patterns scattered throughout the network. The two largest datasets available to date are compiled, and the model uses a simplified molecular-input line-entry system (SMILES) representation. SolPredictor uses the ten-fold split cross-validation Pearson correlation coefficient R2 0.79±0.02 and root mean square error (RMSE) 1.03±0.04. The proposed model was evaluated using five independent datasets. Error analysis, hyperparameter optimization analysis, and model explainability were used to determine the molecular features that were most valuable for prediction.

Suaeda glauca Attenuates Liver Fibrosis in Mice by Inhibiting TGFß1-Smad2/3 Signaling in Hepatic Stellate Cells.

Chronic liver injury due to various hepatotoxic stimuli commonly leads to fibrosis, which is a crucial factor contributing to liver disease-related mortality. Despite the potential benefits of Suaeda glauca (S. glauca) as a natural product, its biological and therapeutic effects are barely known. This study investigated the effects of S. glauca extract (SGE), obtained from a smart farming system utilizing LED lamps, on the activation of hepatic stellate cells (HSCs) and the development of liver fibrosis. C57BL/6 mice received oral administration of either vehicle or SGE (30 or 100 mg/kg) during CCl4 treatment for 6 weeks. The supplementation of SGE significantly reduced liver fibrosis induced by CCl4 in mice as evidenced by histological changes and a decrease in collagen accumulation. SGE treatment also led to a reduction in markers of HSC activation and inflammation as well as an improvement in blood biochemical parameters. Furthermore, SGE administration diminished fibrotic responses following acute liver injury. Mechanistically, SGE treatment prevented HSC activation and inhibited the phosphorylation and nuclear translocation of Smad2/3, which are induced by transforming growth factor (TGF)-ß1 in HSCs. Our findings indicate that SGE exhibits anti-fibrotic effects by inhibiting TGFß1-Smad2/3 signaling in HSCs.

Candidate molecule for premature ejaculation, DA-8031: in vivo and in vitro characterization of DA-8031.

OBJECTIVES: To evaluate the efficacy of DA-8031 against premature ejaculation, we performed in vitro and in vivo pharmacologic studies. METHODS: We used a monoamine transporter binding affinity assay, receptor binding affinity assay, monoamine reuptake inhibition assay, and serotonin uptake inhibition assay in platelets and chemically induced ejaculation models in rats. RESULTS: The present study reports on the pharmacologic profile of the putative antipremature ejaculation drug, DA-8031. DA-8031 exhibits high affinity and selectivity to the serotonin transporter (Ki value 1.94 nM for 5-hydroxytryptamine transporter, 22 020 nM for norepinephrine transporter, and 77 679 nM for dopamine transporter) and potency to inhibit serotonin reuptake into the rat brain synaptosome in vitro (half maximal inhibitory concentration 6.52 nM for 5-hydroxytryptamine, 30.2 µM for norepinephrine, and 136.9 µM for dopamine). In the platelet serotonin uptake study, DA-8031 exhibited significant inhibition at oral doses of 10 and 30 mg/kg in a dose-dependent manner. In the sexual response studies, after oral and intravenous administration of DA-8031, ejaculation was significantly inhibited in both para-chloroamphetamine- and meta-chlorophenylpiperazine-mediated ejaculation models in rats. CONCLUSIONS: The pharmacologic profiles observed in the present study suggest the potential for DA-8031 as a therapeutic agent useful in the treatment of premature ejaculation.