Structural basis of tolvaptan binding to the vasopressin V2 receptor.

The vasopressin V2 receptor (V2R) is a validated therapeutic target for autosomal dominant polycystic kidney disease (ADPKD), with tolvaptan being the first FDA-approved antagonist. Herein, we used Gaussian accelerated molecular dynamics simulations to investigate the spontaneous binding of tolvaptan to both active and inactive V2R conformations at the atomic-level. Overall, the binding process consists of two stages. Tolvaptan binds initially to extracellular loops 2 and 3 (ECL2/3) before overcoming an energy barrier to enter the pocket. Our simulations result highlighted key residues (e.g., R181, Y205, F287, F178) involved in this process, which were experimentally confirmed by site-directed mutagenesis. This work provides structural insights into tolvaptan-V2R interactions, potentially aiding the design of novel antagonists for V2R and other G protein-coupled receptors.

An online target and rapid screening method for α-glucosidase inhibitors based on capillary electrophoresis.

Screening enzymatic active compounds is one of the important fields in drug research. α-Glucosidase can hydrolyze carbohydrates to monosaccharides after meals and lead to the rise of blood glucose levels in human body. Thus, the inhibition of α-glucosidase activity is an effective approach for the diabetes treatment. In this work, we developed a new method to simultaneously screen multiple bioactive compounds within a single CE running. The affect factors on the method performance, including injection, mixing, incubation, separation and detection, were carefully analyzed and discussed. Under the optimum, the mixture consisting of two internal standards (DMSO and 4-nitrophenol) and five compounds (lyoniresinol, hydroxytyrosol, rutin, kaempferol, and quercetin) was simultaneously screened, and kaempferol and quercetin showed stronger activity and this conclusion was also supported by offline assay. Furthermore, molecular docking was employed for investigating its interaction mechanism. Eventually, the established method has been applied to screen potential α-glucosidase inhibitors from an extract of Lycium barbarum and the peak area of rutin, taxifolin, quercetin, and chlorogenic acid in L. barbarum samples changed before and after the enzymatic reaction, confirming that these four compounds had potential inhibitory activities, which was consistent with the literature data. The present work provides a promising method for the target and rapid discovery of bioactive compounds from a plant extract or mixture.

A Molecular Modeling Study of the Hydroxyflutamide Resistance Mechanism Induced by Androgen Receptor Mutations.

Hydroxyflutamide (HF), an active metabolite of the first generation antiandrogen flutamide, was used in clinic to treat prostate cancer targeting androgen receptor (AR). However, a drug resistance problem appears after about one year's treatment. AR T877A is the first mutation that was found to cause a resistance problem. Then W741C_T877A and F876L_T877A mutations were also reported to cause resistance to HF, while W741C and F876L single mutations cannot. In this study, molecular dynamics (MD) simulations combined with the molecular mechanics generalized Born surface area (MM-GBSA) method have been carried out to analyze the interaction mechanism between HF and wild-type (WT)/mutant ARs. The obtained results indicate that AR helix 12 (H12) plays a pivotal role in the resistance of HF. It can affect the coactivator binding site at the activation function 2 domain (AF2, surrounded by H3, H4, and H12). When H12 closes to the AR ligand-binding domain (LBD) like a lid, the coactivator binding site can be formed to promote transcription. However, once H12 is opened to expose LBD, the coactivator binding site will be distorted, leading to invalid transcription. Moreover, per-residue free energy decomposition analyses indicate that N705, T877, and M895 are vital residues in the agonist/antagonist mechanism of HF.

[White light upconversion luminescence and its mechanism of Yb3+/Ho3+/Tm3+ co-doped tellurite glass].

Yb3+ /Ho3+, Yb3+ /Tm3+ and Yb3+ /Ho3+ /Tm3+ co-doped tellurite glasses were prepared by melt-quenching method. Under the excitation of 980 nm laser, Yb3+ /Ho3+/Tm3+ co-doped glass sample shows strong blue, green and red emissions, corresponding to the transitions 1G4 --> 3H6 of Tm3+, 5F4 (5S2) --> 5 I8 of Ho3+, as well as 5F5 -->5 I8 of Ho3+ and 1G4 --> 3F4 of Tm3+ ions, respectively. It was found that the integrated emission intensity ratio of the red to green in Yb3+/Ho3+ /Tm3+ co-doped sample (3.95) is greater than that in Yb3+/Ho3+ co-doped sample (1.69) due to the cross-relaxation between Ho3+ and Tm3+ ions : 3H4 (Tm3+) + 5 I6 (Ho3+) -->3F4 (Tm3+) + 5F5 (Ho3+), and 3F4 (Tm3+ ) + 5 I8 (Ho3+) --> 3H6 (Tm3+) +5 I7 (Ho3+). When the pump power density is 8.2 W x cm(-2), the calculated color coordinates of Yb3+ /Ho3+ /Tm3+ co-doped sample are x = 0.345, y = 0.338, which is very close to the equal energy white light (x = 0.333, y = 0.333).