In a discovery effort to find safe and effective DGAT-1 inhibitors, we have identified 2-phenyloxazole 4-carboxamide 1 as a conformationally constrained analog of a hydrazide hit, which was previously identified from high-throughput screening. Further optimization of this series has led to chemically more stable 2-phenyloxazole-based DGAT-1 inhibitor 25 with improved solubility, cell-based activity, and pharmacokinetic properties. Compound 25 also demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.
State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Free energy perturbation (FEP)-based absolute binding free energy (ABFE) calculations have emerged as a powerful tool for the accurate prediction of ligand-protein binding affinities in drug discovery. The restraint addition is crucial in FEP-ABFE calculations; however, due to the non-orthogonal couplings between the restrained degrees of freedom, it typically requires numerous λ windows to ensure the phase-space overlap during restraint addition. This study introduces the RED-E-function-based equilibrium parameter finder (REPF), a novel method that relies on harmonic restraints to optimize the equilibrium values in restraints, enhancing phase-space overlap and improving the convergence of the restraint addition.
β-glucosidases (BGLs) are key enzymes in the depolymerization of cellulosic biomass, catalyzing the conversion of cello-oligosaccharides into glucose. This conversion is pivotal for enhancing the production of second-generation ethanol or other value-added products in biorefineries. However, the process is often cost-prohibitive due to the high enzyme loadings required.
The Annamite striped rabbit () is an Endangered lagomorph endemic to the Annamite Mountain Range in Vietnam and Laos, with much unknown about its distribution range. In this study, we used previously known records of the Annamite striped rabbit to construct distribution models using Maxent, a modeling approach that has been proven to be robust in identifying potential areas of undiscovered populations of targeted species. Using the optimal model results as a guideline to select the field site, we conducted a systematic camera trap survey in Dak Long Protection Forest, Kon Tum Province, Vietnam.
Introduction: Catheter ablation of persistent atrial fibrillation yields sub-optimal success rates partly due to the considerable heterogeneity within the patient population. Identifying distinct patient phenotypes based on post-ablation prognosis could improve patient selection for additional therapies and optimize treatment strategies.
Methods: We studied all patients who underwent catheter ablation of persistent atrial fibrillation in the DECAAF II trial.
Cardiotoxicity, particularly drug-induced arrhythmias, poses a significant challenge in drug development, highlighting the importance of early-stage prediction of human ether-a-go-go-related gene (hERG) toxicity. hERG encodes the pore-forming subunit of the cardiac potassium channel. Traditional methods are both costly and time-intensive, necessitating the development of computational approaches.
