To enhance the accuracy of virtual screening for bromodomain-containing protein 4 (BRD4) inhibitors, two docking protocols and seven scoring functions were compared. A total of 73 crystal structures of BRD4 (BD1) complexes were selected for analysis. Firstly, docking was carried out using both the LibDock and CDOCKER methods. The CDOCKER protocol was shown to be more effective based on the root mean square deviation (RMSD) values (in Å) between the docking positions and the co-crystal structures, achieving a docking accuracy rate of 86.3%. Then, among the various scoring functions (LigScore1, LigScore2, PLP1, PLP2, PMF, PMF04 and Ludi3), PMF showed the highest correlation with inhibition constants (r2 = 0.614), while Ludi3 scored lowest (r2 = 0.266). Finally, using ligand descriptors from PubChem, a strong correlation (r2 > 0.5) with inhibition constants for heavy atom count was found. Based on these comprehensive evaluations, the PMF scoring function emerged as the best tool for docking-based virtual screening of potential BRD4 (BD1) inhibitors. And the correlation between molecular properties and BRD4 (BD1) ligands also provided information for future design strategies.

Purpose: This is the first-in-human study to investigate the pharmacokinetic and pharmacodynamic profiles, safety, and tolerability of Fazamorexant (a novel dual orexin receptor antagonist) in healthy subjects. Methods: Here, we summarize pharmacokinetic, pharmacodynamic, and safety data from the randomized, double-blind placebo-controlled studies in healthy adults: single ascending doses (2– 80 mg; N = 64), multiple ascending doses (10– 60 mg; N = 40). Results: Following single and multiple dosing, the pharmacokinetic profile was characterized by quick absorption and elimination, with median t_max of 0.625– 1.25 h and arithmetic mean t_1/2 of 1.91– 3.68 h. C_max and AUC_0-t were positively correlated with doses and no apparent Fazamorexant plasma accumulation was detected on Day 7. The hypnotic effects were observed after administration and the effects of high dose groups were slightly higher than that of low dose groups, the results of pharmacodynamics showed a dose-dependent effect and the change in SSS from baseline was greatest in the 80 mg group (2.5). There were no clinically relevant effects of gender on Fazamorexant pharmacokinetics. No serious dose-dependent adverse events (AEs) or deaths were observed during the study. Conclusion: Fazamorexant at a single dose of 2– 80 mg or 10– 60 mg at multiple doses presented satisfactory safety and tolerability in healthy subjects. The findings in this comprehensive first-in-humans study support the continued investigation of Fazamorexant as a therapeutic option for insomnia therapy.

ACC007 is a new-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with favorable pharmacokinetic and safety profiles. NNRTIs are typically administered in combination with two nucleoside reverse transcriptase inhibitors as first-line recommended regimens in several guidelines.

Although cultivation of hybrid rice varieties has been increasing, there are risks that high levels of cadmium (Cd) will accumulate in grain when such rice is grown in Cd-polluted environments. To produce Cd-safe hybrid rice, one practical approach is the generation of low Cd-accumulating parental lines. In two-line hybrid breeding, thermosensitive genic male sterile (TGMS) lines function as female parents to yield hybrid seeds. Recently, Cd accumulation-related genes have been identified; however, the effect of these genes on Cd accumulation in the grains of TGMS lines has yet to be reported. Here, 174 TGMS lines were selected for Cd accumulation phenotyping, and 30 TGMS lines, including 15 stable low-Cd and 15 high-Cd lines, were selected for single-nucleotide polymorphism (SNP) genotyping and association analysis. Association studies were conducted to identify the relationship between Cd accumulation and variable sites within seven candidate Cd-associated genes using logistic models. Nine sequence variant sites in four of the candidate genes were found to be significantly associated with Cd accumulation, two of which in OsNRAMP1 and OsNRAMP5 are low-Cd favorable variants, explaining 46.4% and 22.6% of the phenotypic variation, respectively. These loci could be developed as new molecular markers for identification of Cd accumulation characteristics and low-Cd marker-assisted breeding.